Renal-selective biphenylmethyl imidazole angiotensin II antagonists for treatment of hypertension

ABSTRACT

Renal-selective compounds are described which, in one embodiment, are prodrugs preferentially converted in the kidney to compounds capable of blocking angiotensin II (AII) receptors. These prodrugs are conjugates formed from two components, namely, a first component provided by an AII antagonist compound and a second component which is capable of being cleaved from the first component when both components are chemically linked within the conjugate. The two components are chemically linked by a bond which is cleaved selectively in the kidney, for example, by an enzyme. The liberated AII antagonist compound is then available to block AII receptors within the kidney. Conjugates of particular interest are glutamyl derivatives of biphenylmethyl 1H-substituted imidazole compounds, of which N-acetyl-L-glutamic acid, 5-[[4&#39;-[2-butyl-4-chloro-5-(hydroxymethyl)-1H-imidazol-1-ylmethyl][1,1&#39;-biphenyl]-2-yl]carbonyl]hydrazide (shown below) is an example: ##STR1##

This is a continuation of application Ser. No. 07/566,208 filed Aug. 10,1990, now abandoned.

FIELD OF THE INVENTION

This invention is n the field of cardiovascular therapeutics and relatesto a class of compounds useful in control of hypertension. Of particularinterest is a class of prodrugs of angiotensin II antagonists which,when selectively hydrolyzed in the kidney, provide hypertension control.

BACKGROUND OF THE INVENTION

The renin-angiotensin system is one of the hormonal mechanisms involvedin regulation of pressure/volume homeostasis and in expression ofhypertension. Activation of the renin-angiotensin cascade begins withrenin secretion from the juxtaglomerular apparatus of the kidney andculminates in the formation of angiotensin II, an octapeptide which isthe primary active species of this system. Angiotensin II is a potentvasoconstrictor agent and also produces other physiological effects suchas promoting aldosterone secretion, promoting sodium and fluidretention, inhibiting renin secretion, increasing sympathetic nervoussystem activity, increasing vasopressin secretion, causing positivecardiac inotropic effect and modulating other hormonal systems.

Previous studies have shown that antagonizing angiotensin II at itsreceptors is a viable approach to inhibit the renin-angiotensin system,given the pivotal role of this octapeptide which mediates the actions ofthe renin-angiotensin system through interaction with various tissuereceptors. There are several known angiotensin II antagonists, most ofwhich are peptidic in nature. Such peptidic compounds are of limited usedue to their lack of oral bioavailability or their short duration ofaction. Also, commercially-available peptidic angiotensin II antagonists(e.g., Saralasin) have a significant residual agonist activity whichfurther limit their therapeutic application.

Non-peptidic compounds with angiotensin II antagonist properties areknown. For example, the sodium salt of2-n-butyl-4-chloro-1-(2-chlorobenzyl)imidazole-5-acetic acid hasspecific competitive angiotensin II antagonist activity as shown in aseries of binding experiments, functional assays and in vivo tests [P.C. Wong et al, J. Pharmacol. Exp. Ther., 247(1), 1-7 (1988)]. Also, thesodium salt of 2-butyl-4-choloro-1-(2-nitrobenzyl)imidazole-5-aceticacid has specific competitive angiotensin II antagonist activity asshown in a series of binding experiments, functional assays and in vivotests [A. T. Chiu et al, European J. Pharmacol., 157, 3121 (1988)]. Afamily of 1-benzylimidazole-5-acetate derivatives has been shown to havecompetitive angiotensin II antagonist properties [A. T. Chiu et al, J.Pharmacol. Exp. Ther., 250(3), 867-874 (1989)]. U.S. Pat. No. 4,816,463to Blankey et al describes a family of4,5,6,7-tetrahydro-1H-imidazo(4,5-c)-tetrahydro-pyridine derivativesuseful as antihypertensives, some of which are reported to antagonizethe binding of labelled angiotensin II to rat adrenal receptorpreparation and thus cause a significant decrease in mean arterial bloodpressure in conscious hypertensive rats. EP No. 253,310, published Jan.20, 1988, describes a series of aralkyl imidazole compounds, includingin particular a family of biphenylmethyl substituted imidazoles, asantagonists to the angiotensin II receptor. EP No.323,841 published Jul.12, 1989 describes four classes of angiotensin II antagonists, namely,biphenylmethylpyrroles, biphenylmethylpyrazoles,biphenylmethyl-1,2,3-triazoles and biphenylmethyl4-substituted-4H-1,2,4-triazoles, including the compound3,5-dibutyl-4-[(2'-carboxybiphenyl-4-yl)methyl]-4H-1,2,4-triazole. U.S.Pat. No. 4,880,804 to Carini et al describes a family ofbiphenylmethylbenzimidazole compounds as angiotensin II receptorblockers for use in treatment of hypertension and congestive heartfailure.

One disadvantage of these angiotensin II antagonist compounds is thatthe desired hypertension-reducing effect may be offset byhypotension-induced compensatory stimulation of the renin-angiotensinsystem or stimulation of the sympathetic nervous system, either of whichmay result in promotion of sodium and water retention. Also, someangiotensin II antagonists may have toxicological effects systemicallywhich precludes their use at doses necessary to be effective in reducingblood pressure.

To avoid such systemic side effects, drugs may be targetted to thekidney by creating a conjugate compound that would be a renal-specificprodrug containing the targetted drug modified with a chemical carriermoiety. Cleavage of the drug from the carrier moiety by enzymespredominantly localized in the kidney releases the drug in the kidney.Gamma glutamyl transpeptidase and acylase are examples of such cleavingenzymes found in the kidney which have been used to cleave a targetteddrug from its prodrug carrier within the kidney.

Renal targetted prodrugs are known for delivery of a drug selectively tothe kidney. For example, the compound L-γ-glutamyl amide of dopaminewhen administered to dogs was reported to generate dopamine in vivo byspecific enzymatic cleavage by γ-glutamyl transpeptidase [J. J. Kyncl etal, Adv. Biosc., 20, 369-380 (1979)]. In another study, γ-glutamyl anN-acyl-γ-glutamyl derivatives of the anti-bacterial compoundsulfamethoxazole were shown to deliver relatively high concentrations ofsulfamethoxazole to the kidney which involved enzymatic cleavage of theprodrug by acylamino acid deacylase and γ-glutamyl transpeptidase [M.Orlowski et al, J. Pharmacol. Exp. Ther., 212, 167-172 (1980)]. TheN-γ-glutamyl derivatives of 2-, 3-, or 4-aminophenol andp-fluoro-L-phenylalanine have been found to be readily solvolyzed invitro by γ-glutamyl transpeptidase [S. D. J. Magnan et al, J. Med.Chem., 25, 1018-1021 (1982)]. The hydralazine-like vasodilator2-hydrazino-5-n-butylpyridine (which stimulates guanylate cyclaseactivity) when substituted with the N-acetyl-γ-glutamyl residue resultedin a prodrug which provided selective renal vasodilation [K. G. Hofbaueret al, J. Pharmacol. Exp. Ther., 232, 838-844 (1985)]. The dopamineprodrug γ-L-glutamyl-L-dopa ("gludopa") has been shown to be relativelyspecific for the kidney and to increase renal blood flow, glomerularfiltration and urinary sodium excretion in normal subjects [D. P. Worthet al, Clin. Sci., 69, 207-214 (1985)]. In another study, gludopa wasreported to be an effective renal dopamine prodrug whose activity can beblocked by the dopa-decarboxylase inhibitor carbidopa [R. F. Jeffrey etal, Br. J. Clin. Pharmac., 25, 195-201 (1988)]. A class of 4-ureidoderivatives of isoquinolin-3-ol has been investigated for renal specificeffects such as increases in renal vasodilation and renal blood flow [R.M. Kanojia et al, J. Med. Chem., 32, 990-997 (1989)].

BRIEF DESCRIPTION OF THE DRAWING FIGURES

FIG. 1 is a graph showing reduction in mean arterial pressure byintravenous administration of a conjugate of the invention to aspontaneously hypertensive rat.

FIG. 2 is a graph showing angiotensin II pressor response in aspontaneously hypertensive rat infused by intravenous administrationwith a conjugate of the invention over a period of three days.

FIG. 3 is a graph showing urinary sodium excretion response toangiotensin II infusion in concious normotensive rats followed byadministration of a saline vehicle, an angiotensin II antagonist, or arenal-selective conjugate of the invention.

FIG. 4 is a graph showing mean arterial pressure response to angiotensinII infusion in conscious normotensive rats followed by administration ofa saline vehicle, an angiotensin II antagonist, or a renal-selectiveconjugate of the invention.

DESCRIPTION OF THE INVENTION

Treatment of chronic hypertension or sodium-retaining disorders such ascongestive heart failure, cirrhosis and nephrosis, may be accomplishedby administering to a susceptible or afflicted subject atherapeutically-effective amount of a renal-selective prodrug capable ofcausing blood-pressure reducing effects by selective action in thekidney. An advantage of such renal-selective prodrug therapy resides inreduction or avoidance of adverse side effects associated withsystemically-acting drugs.

Advantages of a renal-selective antihypertensive compound are several.First, the renal-selective compound is targetted at thosepathophysiological mechanisms which occur primarily in the kidney.Second, the regulation of other organ systems is unaffected; thus,normal physiological regulation of other organ systems is maintained.Third, fewer side-effects may be anticipated, since the compound remainsinactive until cleaved in the kidneys. Similarly, fewer negativedrug-drug interactions may be anticipated. Finally, since arenal-selective accumulation of active compound may occur, which is notdependent on plasma levels of the parent compound, lower doses of therenal-selective compound compared to active parent compound may be used.

A renal-selective prodrug is provided by a conjugate comprising aresidue of an angiotensin II antagonist compound, which conjugate isrenal selective. The conjugate will typically comprise a first componentand a second component connected together by a cleavable or hydrolyzablebond. The term "renal-selective", as used to characterize a conjugate ofthe invention, embraces any of the following four pharmacologicalevents: (1) the conjugate is selectively taken up by the kidney and isselectively cleaved in the kidney; (2) the conjugate is not taken upselectively by the kidney, but is selectively cleaved in the kidney; (3)the conjugate is selectively taken up by the kidney and then cleaved inthe kidney; or (4) where the conjugate itself is active as anangiotensin II antagonist, the conjugate is selectively taken up by thekidney without cleavage of the hydrolyzable bond.

The first component of a conjugate of the invention is a residue derivedfrom an antagonist compound capable of inhibiting angiotensin II (AII)receptors, especially those AII receptors located in the kidney. Thesecond residue is capable of being cleaved from the first residuepreferentially. Cleaving of the first and second residues may beaccomplished by a variety of mechanisms. For example, the bond may becleaved by an enzyme in the kidney.

The residue providing the first component may be characterized as the"AII antagonist active" residue. Such "active" residue may be providedby a compound having AII antagonist activity or by a metabolite of suchcompound having AII antagonist activity. The residue providing thesecond component may be characterized in being capable of forming acleavable bond connecting the "active" first residue and the secondresidue. Such bond is cleavable by an enzyme located in the kidney. In apreferred embodiment, this cleavable bond is typically a hydrolyzableamide bond, that is, a bond between a carbonyl-terminated moiety and areactive nitrogen-terminated moiety, such as an amino-terminated moiety,which may be cleaved by an enzyme found in the kidney, but which is notcleaved substantially by enzymes located in other organs or tissues ofthe body. Preferred bond-cleaving enzymes would be found predominantlyin the kidney.

The conjugate containing the residue of an AII antagonist compound andcontaining the cleavable fragment or residue may possess AII antagonistactivity comparable to, or more than, or less than, the AII antagonistcompound which forms the conjugate. In one embodiment of the invention,the conjugate will have AII receptor blocking activity comparable to theAII antagonist component forming the conjugate. In another embodiment ofthe invention, the conjugate will have AII receptor blocking activityless than the AII receptor blocking activity forming the conjugate. Oneadvantage of such differential activity between the conjugate and theAII antagonist component is that certain side effects associated withnon-renal, systemic AII receptor blocking may be avoided or reduced. Forexample, at least one conjugate of the invention has been found to havea very large differential in AII receptor blocking activities betweenthe conjugate and the AII antagonist component forming the conjugate.Such differential activity is advantageous in thattherapeutically-effective antihypertensive doses of the conjugate may beadministered to give renal-selective AII receptor blocking actionresulting from kidney-specific enzyme hydrolysis or metabolism of theconjugate to free the active AII receptor blocker within the kidney.Inasmuch as this renal-selective conjugate has relatively low AIIreceptor blocking activity, compared to the AII receptor compoundforming the conjugate, this conjugate will have fewer adverse sideeffects associated with unwanted systemic interaction with non-renal AIIreceptors such as found in the vascular bed.

DETAILED DESCRIPTION OF THE INVENTION

The first residue of the conjugate may be selected from any class ofcompounds, or metabolites thereof, having angiotensin II antagonistactivity. An example of one such class of angiotensin II antagonistcompounds is provided by a class of biphenylmethyl1H-substituted-1,3-imidazole compounds defined by Formula I: ##STR2##wherein m is a number selected from one to four, inclusive; wherein eachof R⁰ through R¹¹ is independently selected from hydrido, alkyl,hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, formyl,alkoxy, aralkyl, aryl, aroyl, aryloxy, aryloxyalkyl, aralkoxy,alkoxyalkyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkenyl,cycloalkenyl, alkynyl, cyano, nitro, carboxyl, carboxyalkyl,alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl,aralkoxycarbonylalkyl, aralkylcarbonyloxyalkyl, mercaptocarbonyl,mercaptothiocarbonyl, mercaptoalkyl, alkoxycarbonyloxy, alkylthio,cycloalkylthio, alkylthiocarbonyl, alkylcarbonylthio,alkylthiocarbonyloxy, alkylthiocarbonylthio, alkylthiothiocarbonyl,alkylthiothiocarbonylthio, arylthio, arylthiocarbonyl, arylcarbonylthio,arylthiocarbonyloxy, arylthiocarbonylthio, arylthiothiocarbonyl,arylthiothiocarbonylthio, aralkylthio, aralkylthiocarbonyl,aralkylcarbonylthio, aralkylthiocarbonyloxy, aralkylthiocarbonylthio,alkylthiocarbonyl, aralkylthiocarbonylthio, mercapto, alkylsulfinyl,alkylsulfonyl, aralkylsulfinyl, aralkylsulfonyl, arylsulfinyl,arylsulfonyl, phthalimido, phthalimidoalkyl, heteroaryl,heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl andcycloheteroalkylcarbonylalkyl wherein each of said heteroaryl- andcyclohetero-containing groups has one or more ring atoms selected fromoxygen, sulfur and nitrogen atoms, and wherein each of R⁰ through R¹¹may be further independently selected from amino and amido radicals ofthe formula ##STR3## wherein X is oxygen atom or sulfur atom; whereineach n is a number independently selected from zero to six, inclusive;

wherein each of R¹² through R²⁴ is independently selected from hydrido,alkyl, cycloalkyl, cyano, amino, monoalkylamino, dialkylamino,hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, andwherein R¹² and R¹³ taken together, R¹⁴ and R¹⁵ taken together, R¹⁶ andR¹⁷ taken together, R¹⁹ and R²⁰ taken together and R²¹ and R²² takentogether may each form a heterocyclic group having five to seven ringmembers including the nitrogen atom of said amino or amido radical andwhich heterocyclic group may further contain one or more hetero atoms asring members selected from oxygen, nitrogen and sulfur atoms and whichheterocyclic group may be saturated or partially unsaturated; whereinR¹² and R¹³ taken together, R¹⁴ and R¹⁵ taken together, R¹⁹ and R²⁰taken together and R²¹ and R²² taken together may each form an aromaticheterocyclic group having five ring members including the nitrogen atomof said amino or amido radical and which aromatic heterocyclic group mayfurther contain one or more hetero atoms as ring atoms selected fromoxygen, nitrogen and sulfur atoms;

and wherein each of R³ through R¹¹ may be further independently selectedfrom hydrido and haloalkyl, and from acidic moieties of the formula

    -Y.sub.n A

wherein n is a number selected from zero through three, inclusive, andwherein A is an acidic group selected to contain at least one acidichydrogen atom, and the amide, ester and salt derivatives of said acidicmoieties; wherein Y is a spacer group independently selected from one ormore of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, aryl,aralkyl and heteroaryl having one or more ring atoms selected fromoxygen, sulfur and nitrogen atoms;

and wherein any of the foregoing R¹ through R²⁴, Y and A groups having asubstitutable position may be substituted with one or more groupsselected from hydroxy, alkyl, alkenyl, alkynyl, aralkyl, hydroxyalkyl,trifluoromethyl, difluoroalkyl, oxo, alkoxy, aryloxy, aralkoxy,aralkylthio, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aroyl,cycloalkenyl, cyano, cyanoamino, nitro, alkylcarbonyloxy,alkoxycarbonyloxy, alkylcarbonyl, alkoxycarbonyl, carboxyl, mercapto,mercaptocarbonyl, alkylthio, arylthio, alkylthiocarbonyl, alkylsulfinyl,alkylsulfonyl, aralkylsulfinyl, aralkylsulfonyl, arylsulfinyl,arylsulfonyl, heteroaryl having one or more ring atoms selected fromoxygen, sulfur and nitrogen atoms, and amino and amido radicals of theformula ##STR4## wherein X is selected from oxygen atom and sulfur atom;wherein R²⁵ is selected from hydrido, alkyl, cycloalkyl,cycloalkylalkyl, aralkyl, aryl, DR³⁰ and ##STR5## wherein D is selectedfrom oxygen atom and sulfur atom and R³⁰ is selected from hydrido,alkyl, cycloalkyl, cycloalkylalkyl, aralkyl and aryl; wherein each ofR²⁵, R²⁶, R²⁷, R²⁸, R²⁹, R³¹ and R³² is independently selected fromhydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl, haloalkyl,cycloalkylalkyl, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, carboxyl,alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl,haloalkylsulfinyl, haloalkylsulfonyl, aralkyl and aryl, and wherein eachof R²⁶, R²⁷, R²⁸, R²⁹, R³¹ and R³² is further independently selectedfrom amino and amido radicals of the formula ##STR6## wherein X isoxygen atom or sulfur atom; wherein each of R³³, R³⁴, R³⁵, R³⁶, R³⁷ andR³⁸ is independently selected from hydrido, alkyl, cycloalkyl, cyano,amino, monoalkylamino, dialkylamino, hydroxyalkyl, cycloalkylalkyl,alkoxyalkyl, haloalkylsulfinyl, haloalkylsulfonyl, aralkyl and aryl, andwherein R²⁶ and R²⁷ taken together and R²⁸ and R²⁹ taken together mayeach form a heterocyclic group having five to seven ring membersincluding the nitrogen atom of said amino or amido radical, whichheterocyclic group may further contain one or more hetero atoms as ringmembers selected from oxygen, nitrogen and sulfur atoms and whichheterocyclic group may be saturated or partially unsaturated; whereinR²⁶ and R²⁷ taken together and R³¹ and R³² taken together may each forman aromatic heterocyclic group having five ring members including thenitrogen atom of said amino or amido radical and which aromaticheterocyclic group may further contain one or more hetero atoms as ringatoms selected from oxygen, nitrogen and sulfur atoms;

with the proviso that at least one of said R¹ through R²⁴, Y and Asubstituents contains a terminal primary or secondary amino moiety or amoiety convertible to a primary or secondary amino moiety;

or a tautomer thereof or a pharmaceutically-acceptable salt thereof.

Conjugates of the invention are therapeutically effective in treatmentof cardiovascular disorders by acting directly, or by providingcleavable components selected from Formula I compounds which actdirectly, as antagonists to, or blockers of, the angiotensin II (AII)receptor. Thus, conjugates of Formula I would be therapeuticallyeffective in treatment of cardiovascular disorders or would beprecursors to, or prodrugs of, therapeutically-effective compounds.

Preferred compounds of Formula I, from which a cleavable component maybe selected, are all characterized in having a substituent, other thanhydrido, at each of the four- and five-positions of the imidazole ring.Such substituents are selected from the aforementioned R¹ and R² groups.

The phrase "acidic group selected to contain at least one acidichydrogen atom", as used to define the -Y_(n) A moiety, is intended toembrace chemical groups which, when attached to any of the R³ throughR¹¹ positions of Formula I, confers acidic character to the compound ofFormula I. "Acidic character" means proton-donor capability, that is,the capacity of the compound of Formula I to be a proton donor in thepresence of a proton-receiving substance such as water. Typically, theacidic group should be selected to have proton-donor capability suchthat the product compound of Formula I has a pKa in a range from aboutone to about twelve. More typically, the Formula I compound would have apKa in a range from about two to about seven. An example of an acidicgroup containing at least one acidic hydrogen atom is carboxyl group(--COOH). Where n is zero and A is --COOH, in the -Y_(n) A moiety, suchcarboxyl group would be attached directly to one of the R³ through R¹¹positions. The Formula I compound may have one -Y.sub. n A moietyattached at one of the R³ through R¹¹ positions, or may have a pluralityof such -Y_(n) A moieties attached at more than one of the R³ throughR¹¹ positions, up to a maximum of nine such -Y_(n) A moieties. There aremany examples of acidic groups other than carboxyl group, selectable tocontain at least one acidic hydrogen atom. Such other acidic groups maybe collectively referred to as "bioisosteres of carboxylic acid" orreferred to as "acidic bioisosteres". Specific examples of such acidicbioisosteres are described hereinafter. Compounds of Formula I havingthe -Y_(n) A moiety attached at one of positions R⁵, R⁶, R⁸ and R⁹ wouldbe expected to have preferred properties, while attachment at R⁵ or R⁹would be more preferred.

A preferred class of compounds within the sub-class defined by Formula Iconsists of those compounds wherein m is one; wherein each of R⁰ throughR¹¹ is independently selected from alkyl, hydroxyalkyl, halo, haloalkyl,cycloalkyl, cycloalkylalkyl, alkoxy, aralkyl, aryl, aroyl, aryloxy,aryloxyalkyl, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl,alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, cyano, nitro, carboxyl,carboxyalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl,alkoxycarbonylalkyl, aralkoxycarbonylalkyl, aralkylcarbonyloxyalkyl,mercaptocarbonyl, mercaptothiocarbonyl, mercaptoalkyl,alkoxycarbonyloxy, alkylthio, cycloalkylthio, alkylthiocarbonyl,alkylcarbonylthio, alkylthiocarbonyloxy, alkylthiocarbonylthio,alkylthiothiocarbonyl, alkylthiothiocarbonylthio, arylthio,arylthiocarbonyl, arylcarbonylthio, arylthiocarbonyloxy,arylthiocarbonylthio, arylthiothiocarbonyl, arylthiothiocarbonylthio,aralkylthio, aralkylthiocarbonyl, aralkylcarbonylthio,aralkylthiocarbonyloxy, aralkylthiocarbonylthio, aralkylthiocarbonyl,aralkylthiocarbonylthio, mercapto, alkylsulfinyl, alkylsulfonyl,aralkylsulfinyl, aralkylsulfonyl, arylsulfinyl, arylsulfonyl,phthalimido, phthalimidoalkyl, heteroaryl, heteroarylalkyl,cycloheteroalkyl, cycloheteroalkylalkyl andcycloheteroalkylcarbonylalkyl wherein each of said heteroaryl- andcycloheteroalkyl-containing groups has one or more hetero ring atomsselected from oxygen, sulfur and nitrogen atoms, and wherein each of R⁰through R¹¹ may be further independently selected from amino and amidoradicals of the formula ##STR7## wherein X is selected from oxygen atomor sulfur atom; wherein each n is a number independently selected fromzero to six, inclusive;

wherein each of R¹² through R²⁴ is independently selected from hydrido,alkyl, cycloalkyl, cyano, amino, monoalkylamino, dialkylamino,hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl;

and wherein each of R³ through R¹¹ may be further independently selectedfrom hydrido and haloalkyl, and from acidic moieties of the formula

    -Y.sub.n A

wherein n is a number selected from zero through three, inclusive;wherein A is an acidic group selected from acids containing one or moreatoms selected from oxygen, sulfur, phosphorus and nitrogen atoms, andwherein said acidic group is selected to contain at least one acidichydrogen atom, and the amide, ester and salt derivatives of said acidicmoieties; wherein Y is a spacer group independently selected from one ormore of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, aryl,aralkyl and heteroaryl having one or more ring atoms selected fromoxygen, sulfur and nitrogen atoms;

and wherein any of the foregoing R¹ through R²⁴, Y and A groups having asubstitutable position may be substituted with one or more groupsselected from alkyl, alkenyl, aralkyl, hydroxyalkyl, trifluoromethyl,difluoroalkyl, alkoxy, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl,alkoxycarbonyl, carboxyl, mercaptocarbonyl, alkylthio,alkylthiocarbonyl, and amino and amido radicals of the formula ##STR8##wherein X is selected from oxygen atom and sulfur atom; wherein R²⁵ isselected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl,aryl, and DR³⁰ and ##STR9## wherein D is selected from oxygen atom andsulfur atom, and R³⁰ is selected from hydrido, alkyl, cycloalkyl,cycloalkylalkyl, aralkyl and aryl; wherein each of R²⁶, R²⁷, R²⁸, R²⁹,R³¹ and R³² is independently selected from hydrido, alkyl, cycloalkyl,cyano, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, alkanoyl,alkoxycarbonyl, carboxyl, haloalkylsulfinyl, haloalkylsulfonyl, aralkyland aryl, and wherein each of R²⁶, R²⁷, R²⁸, R²⁹, R³¹ and R³² is furtherindependently selected from amino and amido radicals of the formula##STR10## wherein X is selected from oxygen atom or sulfur atom; whereineach of R²⁶ through R³¹ is independently selected from hydrido, alkyl,cycloalkyl, cyano, amino, monoalkylamino, dialkylamino, hydroxyalkyl,cycloalkylalkyl, alkoxyalkyl, haloalkylsulfinyl, haloalkylsulfonyl,aralkyl and aryl;

with the proviso that at least one of said R¹ through R²⁴, Y and Asubstituents contains a terminal primary or secondary amino moiety or amoiety convertible to a primary or secondary amino moiety;

or a tautomer thereof or a pharmaceutically-acceptable salt thereof.

A more preferred class of compounds within the sub-class defined byFormula I consists of those compounds wherein m is one; wherein each ofR⁰ through R¹¹ is independently selected from alkyl, hydroxyalkyl, halo,haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, aralkyl, aryl, aroyl,aryloxy, aryloxyalkyl, aralkoxy, alkoxyalkyl, alkylcarbonyl,alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, cyano,nitro, carboxyl, carboxyalkyl, alkylcarbonyloxy, mercaptocarbonyl,alkoxycarbonyloxy, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl,aralkoxycarbonylalkyl, aralkylcarbonyloxyalkyl, alkylthio,cycloalkylthio, arylthio, aralkylthio, aralkylthiocarbonylthio,mercapto, alkylsulfinyl, alkylsulfonyl, aralkylsulfinyl,aralkylsulfonyl, arylsulfinyl, arylsulfonyl, phthalimido,phthalimidoalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl,cycloheteroalkylalkyl and cycloheteroalklylcarbonylalkyl wherein each ofsaid heteroaryl- and cycloheteroalkyl-containing groups has one or morehetero ring atoms selected from oxygen, sulfur and nitrogen atoms, andwherein each of R⁰ through R¹¹ may be further independently selectedfrom amino and amido radicals of the formula ##STR11## wherein X isselected from oxygen atom or sulfur atom; wherein each n is a numberindependently selected from zero to six, inclusive;

wherein each of R¹² through R²⁴ is independently selected from hydrido,alkyl, cycloalkyl, cyano, amino, monoalkylamino, dialkylamino,hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl;

and wherein each of R³ through R¹¹ may be an acidic moiety furtherindependently selected from hydrido and haloalkyl, and from acidicmoieties of the formula

    -Y.sub.n A

wherein n is a number selected from zero through three, inclusive;

wherein A is selected from carboxylic acid and bioisosteres ofcarboxylic acid selected from ##STR12## wherein each W is independentlyselected from oxygen atom, sulfur atom and NR⁴³ ; wherein each of R³⁹,R⁴⁰, R⁴¹, R⁴² and R⁴³ is independently selected from hydrido, alkyl,haloalkyl, haloalkylsulfonyl, haloalkylcarbonyl, cycloalkyl,cycloalkylalkyl, aryl and aralkyl; wherein each of R³⁹, R⁴⁰, R⁴¹ and R⁴²may be further independently selected from amino radicals of the formula##STR13## wherein each of R⁴⁴ and R⁴⁵ is independently selected fromhydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl,alkoxyalkyl, aralkyl and aryl, and wherein R⁴⁴ and R⁴⁵ taken togethermay form a heterocyclic group having five to seven ring membersincluding the nitrogen atom of said amino radical, which heterocyclicgroup may further contain one or more hetero atoms as ring membersselected from oxygen, nitrogen and sulfur atoms and which heterocyclicgroup may be saturated or partially unsaturated; wherein R⁴⁴ and R⁴⁵taken together may form an aromatic heterocyclic group having five ringmembers including the nitrogen atom of said amino radical and whicharomatic heterocyclic group may further contain one or more hetero atomsas ring atoms selected from oxygen, nitrogen and sulfur atoms; whereineach of R⁴⁰ and R⁴¹ may be further independently selected from hydroxy,alkoxy, alkylthio, aryloxy, arylthio, aralkylthio and aralkoxy; and theamide, ester and salt derivatives of said acidic groups;

wherein said bioisostere of carboxylic acid may be further selected fromheterocyclic acidic groups consisting of heterocyclic rings of four toabout nine ring members, which heterocyclic ring contains at least onehetero atom selected from oxygen, sulfur and nitrogen atoms, whichheterocyclic ring may be saturated, fully unsaturated or partiallyunsaturated, and which heterocyclic ring may be attached at a singleposition selected from R³ through R¹¹ or may be attached at any twoadjacent positions selected from R³ through R¹¹ so as to form afused-ring system with one of the phenyl rings of the biphenyl moiety ofFormula I; and the amide, ester and salt derivatives of saidheterocyclic acidic groups;

wherein Y is a spacer group independently selected from one or more ofalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl and aralkyl;

and wherein any of the foregoing R¹ through R²⁴, Y and A groups having asubstitutable position may be substituted by one or more groups selectedfrom alkyl, difluoroalkyl, alkenyl, aralkyl, hydroxyalkyl,trifluoromethyl, alkoxy, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl,alkoxycarbonyl, carboxyl, mercaptocarbonyl, alkylthio,alkylthiocarbonyl, and amino and amido radicals of the formula ##STR14##wherein X is selected from oxygen atom and sulfur atom; wherein R²⁵ isselected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryland DR³⁰ and ##STR15## wherein D is selected from oxygen atom and sulfuratom, wherein R³⁰ is selected from hydrido, alkyl, cycloalkyl,cycloalkylalkyl, aralkyl and aryl;

wherein each of R²⁶, R²⁷, R²⁸, R²⁹, R³¹ and R³² is independentlyselected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl,haloalkyl, cycloalkylalkyl, alkoxyalkyl, alkanoyl, alkoxycarbonyl,carboxyl, haloalkylsulfinyl, haloalkylsulfonyl, aralkyl and aryl;

with the proviso that at least and A substituents contains a terminalprimary or secondary amino moiety or a moiety convertible to a primaryor secondary amino moiety;

or a tautomer thereof or a pharmaceutically-acceptable salt thereof.

An even more preferred class of compounds within the sub-class definedby Formula I consists of those compounds wherein m is one; wherein eachof R⁰, R¹ and R² is independently selected from alkyl, hydroxyalkyl,halo, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, aralkyl, aryl,aroyl, aryloxy, aryloxyalkyl, aralkoxy, alkoxyalkyl, alkylcarbonyl,alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, cyano,nitro, carboxyl, carboxyalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl,alkoxycarbonylalkyl, aralkoxycarbonylalkyl, aralkylcarbonyloxyalkyl,mercaptocarbonyl, mercaptoalkyl, alkoxycarbonyloxy, alkylthio,cycloalkylthio, arylthio, aralkylthio, mercapto, alkylsulfinyl,alkylsulfonyl, aralkylsulfinyl, aralkylsulfonyl, arylsulfinyl,arylsulfonyl, phthalimido, phthalimidoalkyl, heteroaryl,heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl andcycloheteroalkylcarbonylalkyl wherein each of said heteroaryl- andcycloheteroalkyl-containing groups has one or more hetero ring atomsselected from oxygen, sulfur and nitrogen atoms, and wherein each of R⁰through R¹¹ may be further independently selected from amino and amidoradicals of the formula ##STR16## wherein X is selected from oxygen atomand sulfur atom; wherein each n is a number independently selected fromzero to six, inclusive;

wherein each of R¹² through R²⁴ is independently selected from hydrido,alkyl, cycloalkyl, cyano, amino, monoalkylamino, dialkylamino,hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl;

wherein each of R³ through R¹¹ is independently selected from hydrido,hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl,cycloalkylalkyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aralkoxy,alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, alkenyl, cycloalkenyl,alkynyl, cycloalkynyl, cyano, nitro, carboxyl, alkylthio, aralkylthio,mercapto, alkylsulfinyl, alkylsulfonyl, aralkylsulfinyl,aralkylsulfonyl, arylsulfinyl, arylsulfonyl and heteroaryl having one ormore ring atoms selected from oxygen, sulfur and nitrogen atoms;

and wherein each of R³ through R¹¹ may be an acidic moiety furtherindependently selected from acidic moieties of the formula

    -Y.sub.n A

wherein n is a number selected from zero through three, inclusive;wherein A is selected from carboxylic acid and bioisosteres ofcarboxylic acid selected from ##STR17## wherein each W is independentlyselected from oxygen atom, sulfur atom and NR⁴³ ; wherein each of R³⁹,R⁴² and R⁴³ is independently selected from hydrido, alkyl, haloalkyl,haloalkylsulfonyl, haloalkylcarbonyl, cycloalkyl, cycloalkylalkyl, aryland aralkyl; wherein each of R³⁹ and R⁴² may be further independentlyselected from amino radical of the formula ##STR18## wherein each of R⁴⁴and R⁴⁵ is independently selected from hydrido, alkyl, cycloalkyl,hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl,and wherein R⁴⁴ and R⁴⁵ taken together may form a heterocyclic grouphaving five to seven ring members including the nitrogen atom of saidamino radical, which heterocyclic group may further contain one or morehetero atoms as ring members selected from oxygen, nitrogen and sulfuratoms, and which heterocyclic group may be saturated or partiallyunsaturated; wherein R⁴⁴ and R⁴⁵ taken together may form an aromaticheterocyclic group having five ring members including the nitrogen atomof said amino radical and which aromatic heterocyclic group may furthercontain one or more hetero atoms as ring atoms selected from oxygen,nitrogen and sulfur atoms; and the amide, ester and salt derivatives ofsaid acidic groups; wherein said bioisostere of carboxylic acid may befurther selected from heterocyclic acidic groups consisting ofheterocyclic rings of four to about nine ring members, which ringcontains at least one hetero atom, selected from oxygen, sulfur andnitrogen atoms, which heterocyclic ring may be saturated, fullyunsaturated or partially unsaturated, and which heterocyclic ring may beattached at a single position selected from R³ through R¹¹ or may beattached at any two adjacent positions selected from R³ through R¹¹ soas to form a fused-ring system with one of the phenyl rings of FormulaI; and the amide, ester and salt derivatives of said heterocyclic acidicgroups;

wherein Y is a spacer group independently selected from one or more ofalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl and aralkyl;

wherein each of R¹ through R²⁴, Y and A independently may be substitutedat any substitutable position with one or more groups selected fromalkyl, cycloalkyl, cycloalkylalkyl, hydroxy, oxo, trifluoromethyl,difluoroalkyl, alkoxycarbonyl, cyano, nitro, alkylsulfonyl,haloalkylsulfonyl, aryl, aralkyl, alkoxy, aryloxy and aralkoxy;

with the proviso that at least one of said R¹ through R²⁴, Y and Asubstituents contains a terminal primary or secondary amino moiety or amoiety convertible to a primary or secondary amino moiety;

or a tautomer thereof or a pharmaceutically-acceptable salt thereof.

A highly preferred class of compounds within the sub-class defined byFormula I consists of those compounds wherein m is one; wherein each ofR⁰, R¹ and R² is independently selected from alkyl, hydroxyalkyl, halo,haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, aralkyl, aryl, benzoyl,phenoxy, phenoxyalkyl, phenalkyloxy, phenylthio, phenalkylthio,aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, alkenyl,cycloalkenyl, alkynyl, cyano, nitro, carboxyl, carboxyalkyl,alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl,aralkoxycarbonylalkyl, aralkylcarbonyloxyalkyl, mercaptocarbonyl,mercaptoalkyl, alkoxycarbonyloxy, alkylthio, cycloalkylthio,phthalimido, phthalimidoalkyl, heteroaryl, heteroarylalkyl,cycloheteroalkyl, cycloheteroalkylalkyl andcycloheteroalkylcarbonylalkyl wherein each of said heteroaryl- andcycloheteroalkyl-containing groups has one or more hetero ring atomsselected from oxygen, sulfur and nitrogen atoms, and wherein each of R⁰through R¹¹ may be further independently selected from amino and amidoradicals of the formula ##STR19## wherein X is selected from oxygen atomand sulfur atom; wherein each n is a number independently selected fromzero to six, inclusive;

wherein each of R¹² through R²⁴ is independently selected from hydrido,alkyl, cycloalkyl, cyano, amino, hydroxyalkyl, alkoxyalkyl, phenalkyland phenyl;

wherein each of R³ through R¹¹ is independently selected from hydrido,hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl,cycloalkylalkyl, alkoxy, phenalkyl, phenyl, benzoyl, phenoxy,phenalkyloxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, alkenyl,cyano, nitro, carboxyl, alkylthio, mercapto and heteroaryl having one ormore ring atoms selected from oxygen, sulfur and nitrogen atoms;

and wherein each of R³ through R¹¹ may be an acidic moiety furtherindependently selected from acidic moieties of the formula

    -Y.sub.n A

wherein n is a number selected from zero through two, inclusive; whereinA is selected from carboxylic acid and bioisosteres of carboxylic acidselected from ##STR20## wherein each W is independently selected fromoxygen atom, sulfur atom and NR⁴³ ; wherein each of R³⁹, R⁴² and R⁴³ isindependently selected from hydrido, alkyl, haloalkyl,haloalkylsulfonyl, haloalkylcarbonyl, cycloalkyl, phenyl and benzyl;wherein each of R³⁹ and R⁴² may be further independently selected fromamino radical of the formula ##STR21## wherein each of R⁴⁴ and R⁴⁵ isindependently selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl,haloalkyl, alkoxyalkyl, benzyl and phenyl; and the amide, ester and saltderivatives of said acidic groups;

wherein said bioisostere of carboxylic acid may be further selected fromheterocyclic acidic groups consisting of heterocyclic rings of four toabout nine ring members, which ring contains at least one hetero atom,selected from oxygen, sulfur and nitrogen atoms, which heterocyclic ringmay be saturated, fully unsaturated or partially unsaturated, and whichheterocyclic ring may be attached at a single position selected from R³through R¹¹ or may be attached at any two adjacent positions selectedfrom R³ through R¹¹ so as to form a fused-ring system with one of thephenyl rings of the biphenyl moiety of Formula I; and the amide, esterand salt derivatives of said heterocyclic acidic groups;

wherein Y is a spacer group independently selected from one or more ofalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, phenyl, phenalkyl andaralkyl;

wherein each of R¹ through R²⁴, Y and A and independently may besubstituted at any substitutable position with one or more groupsselected from alkyl, cycloalkyl, cycloalkylalkyl, hydroxy, oxo,trifluoromethyl, difluoroalkyl, alkoxycarbonyl, cyano, nitro,alkylsulfonyl, haloalkylsulfonyl, aryl, aralkyl, alkoxy, aryloxy andaralkoxy;

with the proviso that at least one of said R¹ through R²⁴, Y and Asubstituents contains a terminal primary or secondary amino moiety or amoiety convertible to a primary or secondary amino moiety;

or a tautomer thereof or a pharmaceutically-acceptable salt thereof.

An even more highly preferred class of compounds within Formula Iconsists of those compounds wherein m is one; wherein R⁰ is selectedfrom alkyl, alkenyl, phenyl, alkylthio, cycloalkyl, cycloalkylalkyl andcycloalkylthio; wherein each of R¹ and R² is independently selected fromalkyl, aminoalkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl,cycloalkylalkyl, alkoxy, aralkyl, aryl, benzoyl, phenoxy, phenoxyalkyl,phenalkyloxy, phenylthio, phenalkylthio, aralkoxy, alkoxyalkyl, acetyl,alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cyano, nitro, carboxyl,carboxyalkyl, alkylcarbonyloxy, mercaptoalkyl, mercaptocarbonyl,alkoxycarbonyloxy, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl,aralkoxycarbonylalkyl, aralkylcarbonyloxyalkyl, phthalimido,phthalimidoalkyl, imidazoalkyl, tetrazole, tetrazolealkyl, alkylthio,cycloalkylthio, and amino and amido radicals of the formula ##STR22##wherein X is selected from oxygen atom and sulfur atom; wherein each nis a number independently selected from zero to six, inclusive;

wherein each of R¹² through R²⁴ is independently selected from hydrido,alkyl, cycloalkyl, cyano, amino, hydroxyalkyl, alkoxyalkyl, phenalkyland phenyl;

wherein each of R³ through R¹¹ is independently selected from hydrido,hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl,cycloalkylalkyl, alkoxy, phenalkyl, phenyl, benzoyl, phenoxy,phenalkyloxy, alkoxyalkyl, acetyl, alkoxycarbonyl, alkenyl, cyano,nitro, carboxyl, alkylthio and mercapto;

and wherein each of R³ through R¹¹ may be an acidic moiety furtherindependently selected from acidic moieties consisting of CO₂ H, CO₂CH₃, SH, CH₂ SH, C₂ H₄ SH, PO₃ H₂, NHSO₂ CF₃, NHSO₂ C₆ F₅, SO₃ H,CONHNH₂, CONHNHSO₂ CF₃, CONHOCH₃, CONHOC₂ H₅, CONHCF₃, OH, CH₂ OH, C₂ H₄OH, OPO₃ H₂, OSO₃ H , ##STR23## wherein each of R⁴⁶, R⁴⁷ and R⁴⁸ isindependently selected from H, Cl, CN, NO₂, CF₃, C₂ F₅, C₃ F₇, CHF₂,CH₂F, CO₂ CH₃, CO₂ C₂ H₅, SO₂ CH₃, SO₂ CF₃ and SO₂ C₆ F₅ ; wherein Z isselected from O, S, NR⁴⁹ and CH₂ ; wherein R⁴⁹ is selected from hydrido,CH₃ and CH₂ C₆ H₅ ; and wherein said acidic moiety may be a heterocyclicacidic group attached at any two adjacent positions of R³ through R¹¹ soas to form a fused ring system so as to include one of the phenyl ringsof the biphenyl moiety of Formula I, said biphenyl fused ring systemselected from ##STR24## and the esters, amides and salts of said acidicmoieties; with the proviso that at least one of said R¹ through R²⁴substituents contains a terminal primary or secondary amino moiety or amoiety convertible to a primary or secondary amino moiety;

or a tautomer thereof or a pharmaceutically-acceptable salt thereof.

A class of compounds of particular interest within Formula I consists ofthose compounds wherein m is one; wherein R⁰ is selected from C₄ H₉ (n),CH₃ CH₂ CH═CH, C₃ H₇ (n), SC₃ H₇, ##STR25## C₂ H₅, C₅ H₁₁ (n), C₆ H₁₃(n), SC₄ H₉, ##STR26## CH₃ CH═CH and CH₃ CH₂ CH₂ CH═CH--; wherein eachof R¹ and R² is independently selected from amino, aminomethyl,aminoethyl, aminopropyl, CH₂ OH, CH₂ OCOCH₃, CH₂ Cl, Cl, CH₂ OCH₃, CH₂OCH(CH₃)₂, I, CHO, CH₂ CO₂ H, CH(CH₃)CO₂ H, NO₂, Cl, ##STR27## CO₂ CH₃,--CONH₂, --CONHCH₃, CON(CH₃)₂, --CH₂ --NHCO₂ C₂ H₅, ##STR28## --CH₂NHCO₂ CH₃, --CH₂ NHCO₂ C₃ H₇, --CH₂ NHCO₂ CH₂ (CH₃)₂, --CH₂ NHCO₂ C₄ H₉,CH₂ NHCO₂ -adamantyl, --CH₂ NHCO₂ --(1-napthyl), --CH₂ NHCONHCH₃, --CH₂NHCONHC₂ H₅, --CH₂ NHCONHC₃ H₇, --CH₂ NHCONHC₄ H₉, --CH₂ NHCONHCH(CH₃)₂,--CH₂ NHCONH(1-napthyl), --CH₂ NHCONH(1-adamantyl), CO₂ H, ##STR29##--CH₂ CH₂ CH₂ CO₂ H, --CH₂ CH₂ F, --CH₂ OCONHCH₃, --CH₂ OCSNHCH₃, --CH₂NHCSOC₃ H₇, --CH₂ CH₂ CH₂ F, --CH₂ ONO₂, ##STR30## --CH₂ SH, ##STR31##H, Cl, NO₂, CF₃, CH₂ OH, Br, F, I, methyl, ethyl, n-propyl, isopropyl,n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl,neopentyl, phenyl, benzyl, phenethyl, cyclohexyl, cyclohexylmethyl,1-oxoethyl, 1-oxopropyl, 1-oxobutyl, 1-oxopentyl, 1,1-dimethoxypropyl,1,1-dimethoxybutyl, 1,1-dimethoxypentyl, hydroxyalkyl, halo,difluoromethyl, 1,1-difluoroethyl, 1,1-difluoropropyl, 1,1-difluorobutyland 1,1-difluoropentyl; wherein each of R³ through R¹¹ is hydrido, withthe proviso that at least one of R⁵, R⁶, R⁸ and R⁹ is an acidic groupselected from CO₂ H, SH, PO₃ H₂, SO₃ H, CONHNH₂, CONHNHSO₂ CF₃, OH,##STR32## wherein each of R⁴⁶ and R⁴⁷ is independently selected from Cl,CN, NO₂, CF₃, CO₂ CH₃ and SO₂ CF₃ ;

with the proviso that at least one of said R¹ through R¹¹ substituentscontains a terminal primary or secondary amino moiety or a moietyconvertible to a primary or secondary amino moiety;

or a tautomer thereof or a pharmaceutically-acceptable salt thereof.

A class of compounds of more particular interest within Formula Iconsists of these compounds wherein m is one; wherein R⁰ is selectedfrom C₄ H₉ (n), CH₃ CH₂ CH═CH, C₃ H₇ (n), SC₃ H₇, ##STR33## C₂ H₅, C₅H₁₁ (n), C₆ H₁₃ (n), SC₄ H₉, ##STR34## CH₃ CH═CH and CH₃ CH₂ CH₂CH═CH--; wherein R¹ is selected from amino, aminomethyl, aminoethyl,aminopropyl, CH₂ OH, CH₂ OCOCH₃, CH₂ Cl, Cl, CH₂ OCH₃, CH₂ OCH(CH₃)₂, I,CHO, CH₂ CO₂ H, CH(CH₃)CO₂ H, --CO₂ CH₃, CONH₂, --CONHCH₃, CON(CH₃)₂,CH₂ --NHCO₂ C₂ H₅, ##STR35## --CH₂ NHCO₂ CH₃, --CH₂ NHCO₂ C₃ H₇, --CH₂NHCO₂ CH₂ (CH₃)₂, --CH₂ NHCO₂ C₄ H₉, CH₂ NHCO₂ -adamantyl, --CH₂ NHCO₂-(1-napthyl), --CH₂ NHCONHCH₃, --CH₂ NHCONHC₂ H₅, --CH₂ NHCONHC₃ H₇,--CH₂ NHCONHC₄ H₉, --CH₂ NHCONHCH(CH₃)₂, --CH₂ NHCONH(1-napthyl), --CH₂NHCONH(1-adamantyl), CO₂ H, ##STR36## --CH₂ CH₂ CH₂ CO₂ H, --CH₂ CH₂ F,CH₂ OCONHCH₃, --CH₂ CH₂ CH₂ F, --CH₂ SH and ##STR37## wherein R² isselected from H, Cl, NO₂, CF₃, CH₂ OH, Br, F, I, methyl, ethyl,n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl,isopentyl, neopentyl, phenyl, benzyl, phenethyl, cyclohexyl,cyclohexylmethyl, 1-oxoethyl, 1-oxopropyl, 1-oxobutyl, 1-oxopentyl,1,1-dimethoxypropyl, 1,1-dimethoxybutyl, 1,1-dimethoxypentyl,hydroxyalkyl, halo, difluoromethyl, 1,1-difluoroethyl,1,1-difluoropropyl, 1,1-difluorobutyl and 1,1-difluoropentyl; whereineach of R³ through R¹¹ is hydrido, with the proviso that at least one ofR⁵, R⁶, R⁸ and R⁹ is an acidic group selected from CO₂ H, SH, PO₃ H₂,SO₃ H, CONHNH₂, CONHNHSO₂ CF₃, OH, ##STR38## wherein each of R⁴⁶ and R⁴⁷is independently selected from Cl, CN, NO₂, CF₃, CO₂ CH₃ and SO₂ CF₃ ;

with the proviso that at least one of said R¹ through substituentscontains a terminal primary or secondary amino moiety or a moietyconvertible to a primary or secondary amino moiety;

or a tautomer thereof or a pharmaceutically-acceptable salt thereof.

A class of compounds of even more particular interest within Formula Iconsists of those compounds wherein m is one wherein R⁰ is selected fromC₄ H₉ (n), CH₃ CH₂ CH═CH, C₃ H₇ (N), SC₃ H₇, ##STR39## C₂ H₅, C₅ H₁₁(n), C₆ H₁₃ (n), SC₄ H₉, ##STR40## CH₃ CH═CH and CH₃ CH₂ CH₂ CH═CH--;wherein R¹ is selected from H, Cl, NO₂, CF₃, CH₂ OH, Br, F, I, methyl,ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl,n-pentyl, isopentyl, neopentyl, phenyl, benzyl, phenethyl, cyclohexyl,cyclohexylmethyl, 1-oxoethyl, 1-oxopropyl, 1-oxobutyl, 1-oxopentyl,1,1-dimethoxypropyl, 1,1-dimethoxybutyl, 1,1-dimethoxypentyl,hydroxyalkyl, halo, difluoromethyl, 1,1-difluoroethyl,1,1-difluoropropyl, 1,1-difluorobutyl and 1,1-difluoropentyl; wherein R²is selected from amino, aminomethyl, aminoethyl, aminopropyl, CH₂ OH,CH₂ OCOCH₃, CH₂ Cl, Cl, CH₂ OCH₃, CH₂ OCH(CH₃)₂, I, CHO, CH₂ CO₂ H,CH(CH₃)CO₂ H, , --CO₂ CH₃, --CONH₂, --CONHCH₃, CON(CH₃)₂, --CH₂ --NHCO₂C₂ H₅, ##STR41## --CH₂ NHCO₂ CH₃, --CH₂ NHCO₂ C₃ H₇, --CH₂ NHCO₂ CH₂(CH₃)₂, --CH₂ NHCO₂ C₄ H₉, CH₂ NHCO₂ -adamantyl, --CH₂ NHCO₂-(1-napthyl), --CH₂ NHCONHCH₃, --CH₂ NHCONHC₂ H₅, --CH₂ NHCONHC₃ H₇,--CH₂ NHCONHC₄ H₉, --CH₂ NHCONHCH(CH₃)₂, --CH₂ NHCONH(1-napthyl), --CH₂NHCONH(1-adamantyl), CO₂ H, ##STR42## --CH₂ CH₂ CH₂ CO₂ H, --CH₂ CH₂ F,--CH₂ OCONHCH₃, --CH₂ CH₂ CH₂ F, --CH₂ SH and wherein each of R³ throughR¹¹ is hydrido, with the proviso that at least one of R⁵, R⁶, R⁸ and R⁹is an acidic group selected from CO₂ H, SH, PO₃ H₂, SO₃ H, CONHNH₂,CONHNHSO₂ CF₃, OH, ##STR43## wherein each of R⁴⁶ and R⁴⁷ isindependently selected from Cl, CN, NO₂, CF₃, CO₂ CH₃ and SO₂ CF₃ ;

with the proviso that at least one of said R¹ through R¹¹ substituentscontains a terminal primary or secondary amino moiety or a moietyconvertible to a primary or secondary amino moiety;

or a tautomer thereof or a pharmaceutically-acceptable salt thereof.

The second component of a conjugate of the invention is provided by aresidue which forms a kidney-enzyme-cleavable amide bond with theresidue of the first-component AII antagonist compound. Such residue ispreferably selected from a class of compounds of Formula II: ##STR44##wherein each of R⁵⁰ and R⁵¹ may be independently selected from hydrido,alkylcarbonyl, alkoxycarbonyl, alkoxyalkyl, hydroxyalkyl and haloalkyl;and wherein G is selected from hydroxyl, halo, mercapto, --OR⁵², --SR⁵³and ##STR45## wherein each of R⁵², R⁵³ and R⁵⁴ is independently selectedfrom hydrido and alkyl; with the proviso that said Formula II compoundis selected such that formation of the cleavable amide bond occurs atcarbonyl moiety attached at the gamma-position carbon of said Formula IIcompound.

More preferred are compounds of Formula II wherein each G is hydroxy.

A more highly preferred class of compounds within Formula II consists ofthose compounds wherein each G is hydroxy; wherein R⁵⁰ is hydrido; andwherein R⁵¹ is selected ##STR46## wherein R⁵⁵ is selected from methyl,ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl,n-pentyl, neopentyl, n-hexyl and chloromethyl.

A most highly preferred compound of Formula II is N-acetyl-γ-glutamicacid which provides a residue for the second component of a conjugate ofthe invention as shown below: ##STR47##

The phrase "terminal primary or secondary amino moiety or a moietyconvertible to a primary or secondary amino terminal moiety"characterizes a structural requirement for selection of a suitableangiotensin II antagonist compound as the "active" first residue of aconjugate of the invention. Such terminal amino moiety must be availableto react with a terminal carboxylic moiety of the cleavable secondresidue to form a kidney-enzyme-specific hydrolyzable bond.

In one embodiment of the invention, the first component used to form aconjugate of the invention provides a first residue derived from an AIIantagonist compound containing a terminal primary or secondary aminomoiety. Examples of such terminal amino moiety are amino and linear orbranched aminoalkyl moieties containing linear or branched alkyl groupssuch as aminomethyl, aminoethyl, aminopropyl, aminoisopropyl,aminobutyl, aminosecbutyl, aminoisobutyl, aminotertbutyl, aminopentyl,aminoisopentyl and aminoneopentyl.

In another embodiment of the invention, the first component used to formthe conjugate of the invention provides a first residue derived from anAII antagonist compound containing a moiety convertible to a primary orsecondary amino terminal moiety. An example of a moiety convertible toan amino terminal moiety is a carboxylic acid group reacted withhydrazine so as to convert the acid moiety to carboxylic acid hydrazide.The hydrazide moiety thus contains the terminal amino moiety which maythen be further reacted with the carboxylic acid containing residue ofthe second component to form a hydrolyzable amide bond. Such hydrazidemoiety thus constitutes a "linker" group between the first and secondcomponents of a conjugate of the invention.

Suitable linker groups may be provided by a class of diamino-terminatedlinker groups based on hydrazine as defined by Formula III: ##STR48##wherein each of R²⁰⁰ and R²⁰¹ may be independently selected fromhydrido, alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, hydroxyalkyl,aralkyl, aryl, haloalkyl, amino, monoalkylamino, dialkylamino,cyanoamino, carboxyalkyl, alkylsulfino, alkylsulfonyl, arylsulfinyl andarylsulfonyl; and wherein n is zero or a number selected from threethrough seven, inclusive. In Table I there is shown a class of specificexamples of diamino-terminated linker groups within Formula III,identified as Linker Nos. 1-73. These linker groups would be suitable toform a conjugate between a carbonyl moiety of an AII antagonist(designated as "I") and a carbonyl moiety of a carbonyl terminatedsecond residue such as the carbonyl moiety attached to the gamma carbonof a glutamyl residue (designated as "T").

                  TABLE I                                                         ______________________________________                                         ##STR49##                                                                    I = inhibitor                                                                 T = acetyl-γ-glutamyl                                                   LINKER                                                                        NO.      n        R.sup.200    R.sup.201                                      ______________________________________                                         1       0        H            H                                               2       0        CH.sub.3     H                                               3       0        C.sub.2 H.sub.5                                                                            H                                               4       0        C.sub.3 H.sub.7                                                                            H                                               5       0        CH(CH.sub.3).sub.2                                                                         H                                               6       0        C.sub.4 H.sub.9                                                                            H                                               7       0        CH(CH.sub.3)CH.sub.2 CH.sub.3                                                              H                                               8       0        C(CH.sub.3).sub.3                                                                          H                                               9       0        C.sub.5 H.sub.9                                                                            H                                              10       0        C.sub.6 H.sub.11 (cyclo)                                                                   H                                              11       0        C.sub.6 H.sub.5                                                                            H                                              12       0        CH.sub.2 C.sub.6 H.sub.5                                                                   H                                              13       0        H            CH.sub.3                                       14       0        H            C.sub.2 H.sub.5                                15       0        H            C.sub.3 H.sub.7                                16       0        H            CH(CH.sub.3).sub.2                             17       0        H            C.sub.4 H.sub.9                                18       0        H            CH(CH.sub.3)CH.sub.2 CH.sub.3                  19       0        H            C(CH.sub.3).sub.3                              20       0        H            C.sub.5 H.sub.9                                21       0        H            C.sub.6 H.sub.13                               22       0        H            C.sub.6 H.sub.5                                23       0        H            CH.sub.2 C.sub.6 H.sub.5                       24       0        H            C.sub.6 H.sub.11 (cyclo)                       25       0        C.sub.6 H.sub.13                                                                           H                                              26       0        CH.sub.3     CH.sub.3                                       27       0        C.sub.2 H.sub.5                                                                            C.sub.2 H.sub.5                                28       0        C.sub.3 H.sub.7                                                                            C.sub.3 H.sub.7                                29       0        CH(CH.sub.3).sub.2                                                                         CH(CH.sub.3).sub.2                             30       0        C.sub.4 H.sub.9                                                                            C.sub.4 H.sub.9                                31       0        CH(CH.sub.3)CH.sub.2 CH.sub.3                                                              CH(CH.sub.3)CH.sub.2 CH.sub.3                  32       0        C(CH.sub.3).sub.3                                                                          C(CH.sub.3).sub.3                              33       0        C.sub.5 H.sub.9                                                                            C.sub.5 H.sub.9                                34       0        C.sub.6 H.sub.13                                                                           C.sub.6 H.sub.13                               35       0        C.sub.6 H.sub.11 (cyclo)                                                                   C.sub.6 H.sub.11 (cyclo)                       36       0        C.sub.6 H.sub.5                                                                            C.sub.6 H.sub.5                                37       0        CH.sub.2 C.sub.6 H.sub.5                                                                   CH.sub.2 C.sub.6 H.sub.5                       38       3        H            H                                              39       3        CH.sub.3     H                                              40       3        H            CH.sub.3                                       41       3        C.sub.6 H.sub.5                                                                            H                                              42       3        H            C.sub.6 H.sub.5                                43       3        CH.sub.3     C.sub.6 H.sub.5                                44       3        C.sub.6 H.sub.5                                                                            CH.sub.3                                       45       3        CH.sub.2 C.sub.6 H.sub.5                                                                   H                                              46       3        H            CH.sub.2 C.sub.6 H.sub.5                       47       4        H            H                                              48       4        CH.sub.3     H                                              49       4        H            CH.sub.3                                       50       4        C.sub.6 H.sub.5                                                                            H                                              51       4        H            C.sub.6 H.sub.5                                52       4        CH.sub.3     C.sub.6 H.sub.5                                53       4        C.sub.6 H.sub.5                                                                            CH.sub.3                                       54       4        CH.sub.2 C.sub.6 H.sub.5                                                                   H                                              55       4        H            CH.sub.2 C.sub.6 H.sub.5                       56       5        H            H                                              57       5        CH.sub.3     H                                              58       5        H            CH.sub.3                                       59       5        C.sub.6 H.sub.5                                                                            H                                              60       5        H            C.sub.6 H.sub.5                                61       5        CH.sub.3     C.sub.6 H.sub.5                                62       5        C.sub.6 H.sub.5                                                                            CH.sub.3                                       63       5        CH.sub.2 C.sub.6 H.sub.5                                                                   H                                              64       5        H            CH.sub.2 C.sub.6 H.sub.5                       65       6        H            H                                              66       6        CH.sub.3     H                                              67       6        H            CH.sub.3                                       68       6        C.sub.6 H.sub.5                                                                            H                                              69       6        H            C.sub.6 H.sub.5                                70       6        CH.sub.3     C.sub.6 H.sub.5                                71       6        C.sub.6 H.sub.5                                                                            CH.sub.3                                       72       6        CH.sub.2 C.sub.6 H.sub.5                                                                   H                                              73       6        H            CH.sub.2 C.sub.6 H.sub.5                       ______________________________________                                    

Another class of suitable diamino terminal linker groups is defined byFormula IV: ##STR50## wherein each of Q and T is one or more groupsindependently selected from ##STR51## wherein each of R²⁰² through R²⁰⁵is independently selected from hydrido, hydroxy, alkyl, cycloalkyl,cycloalkylalkyl, aralkyl, aryl, alkoxy, aralkoxy, aryloxy, alkoxyalkyl,haloalkyl, hydroxyalkyl, halo, cyano, amino, monoalkylamino,dialkylamino, carboxy, carboxyalkyl, alkanoyl, alkenyl, cycloalkenyl andalkynyl.

A preferred class of linker groups within Formula IV is defined byFormula V: ##STR52## wherein each of R²⁰² and R²⁰³ is independentlyselected from hydrido, hydroxy, alkyl, phenalkyl, phenyl, alkoxy,benzyloxy, phenoxy, alkoxyalkyl, hydroxyalkyl, halo, amino,monoalkylamino, dialkylamino, carboxy, carboxyalkyl and alkanoyl; andwherein each of p and q is a number independently selected from onethrough six, inclusive; with the proviso that when each of R²⁰² and R²⁰³is selected from halo, hydroxy, amino, monoalkylamino and dialkylamino,then the carbon to which R²⁰² or R²⁰³ is attached in Formula V is notadjacent to a nitrogen atom of Formula V.

A more preferred class of linker groups of Formula V consists ofdivalent radicals wherein each of R²⁰² and R²⁰³ is independentlyselected from hydrido, hydroxy, alkyl, alkoxy, amino, monoalkylamino,carboxy, carboxyalkyl and alkanoyl; and wherein each of p and q is anumber independently selected from two through four, inclusive. Evenmore preferred are linker groups wherein each of R²⁰² and R²⁰³ isindependently selected from hydrido, amino, monoalkylamino and carboxyl;and wherein each of p and q is independently selected from the numberstwo and three. Most preferred is a linker group wherein each of R²⁰² andR²⁰³ is hydrido; and wherein each of p and q is two; such most preferredlinker group is derived from a piperazinyl group and has the structure##STR53##

In Table II there is shown a class of specific examples of cyclized,diamino-terminated linker groups within Formula V. These linker groups,identified as Linker Nos. 74-95, would be suitable to form a conjugatebetween a carbonyl moiety of an AII antagonist (designated as "I") and acarbonyl moiety of carbonyl terminated second residue such as thecarbonyl moiety attached to the gamma carbon of a glutamyl residue(designated as "T").

                                      TABLE II                                    __________________________________________________________________________     ##STR54##                                                                    I = inhibitor                                                                 T = acetyl-γ-glutamyl                                                   LINKER                                                                        NO.  R.sup.206                                                                          R.sup.207                                                                        R.sup.208                                                                          R.sup.209                                                                        R.sup.210                                                                          R.sup.211                                                                        R.sup.212                                                                          R.sup.213                                   __________________________________________________________________________    74   H    H  H    H  H    H  H    H                                           75   CH.sub.3                                                                           H  H    H  H    H  H    H                                           76   H    H  H    H  CH.sub.3                                                                           H  H    H                                           77   CH.sub.3                                                                           H  H    H  CH.sub.3                                                                           H  H    H                                           78   CH.sub.3                                                                           H  CH.sub.3                                                                           H  H    H  H    H                                           79   CH.sub.3                                                                           H  H    H  H    H  CH.sub.3                                                                           H                                           80   CH.sub.3                                                                           CH.sub.3                                                                         H    H  H    H  H    H                                           81   H    H  H    H  CH.sub.3                                                                           CH.sub.3                                                                         H    H                                           82   CH.sub.3                                                                           CH.sub.3                                                                         H    H  CH.sub.3                                                                           CH.sub.3                                                                         H    H                                           83   CH.sub.3                                                                           CH.sub.3                                                                         CH.sub.3                                                                           CH.sub.3                                                                         H    H  H    H                                           84   CH.sub.3                                                                           CH.sub.3                                                                         H    H  H    H  CH.sub.3                                                                           CH.sub.3                                    85   H    H  H    H  CH.sub.3                                                                           CH.sub.3                                                                         CH.sub.3                                                                           CH.sub.3                                    86   C.sub.6 H.sub.5                                                                    H  H    H  H    H  H    H                                           87   H    H  H    H  C.sub.6 H.sub.5                                                                    H  H    H                                           88   C.sub.6 H.sub.5                                                                    H  H    H  C.sub.6 H.sub.5                                                                    H  H    H                                           89   C.sub.6 H.sub.5                                                                    H  H    H  H    H  C.sub.6 H.sub.5                                                                    H                                           90   C.sub.6 H.sub.5                                                                    H  C.sub.6 H.sub.5                                                                    H  H    H  H    H                                           91   CH.sub.2 C.sub.6 H.sub.5                                                           H  H    H  H    H  H    H                                           92   H    H  H    H  CH.sub.2 C.sub.6 H.sub.5                                                           H  H    H                                           93   CH.sub.2 C.sub.6 H.sub.5                                                           H  H    H  CH.sub.2 C.sub.6 H.sub.5                                                           H  H    H                                           94   CH.sub.2 C.sub.6 H.sub.5                                                           H  H    H  H    H  CH.sub.2 C.sub.6 H.sub.5                                                           H                                           95   CH.sub.2 C.sub.6 H.sub.5                                                           H  CH.sub.2 C.sub. 6 H.sub.5                                                          H  H    H  H    H                                           __________________________________________________________________________

Another class of suitable diamino terminal linker groups is defined byFormula VI: ##STR55## wherein each of R²¹⁴ through R²¹⁷ is independentlyselected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl,alkoxyalkyl, aralkyl, aryl, haloalkyl, amino, monoalkylamino,dialkylamino, cyanoamino, carboxyalkyl, alkylsulfino, alkylsulfonyl,arylsulfinyl and arylsulfonyl; and wherein p is a number selected fromone through six inclusive.

A preferred class of linker groups within Formula VI consists ofdivalent radicals wherein each of R²¹⁴ and R²¹⁵ is hydrido; wherein eachof R⁶² and R⁶³ is independently selected from hydrido, alkyl, phenalkyl,phenyl, alkoxyalkyl, hydroxyalkyl, haloalkyl and carboxyalkyl; andwherein p is two or three. A more preferred class of linker groupswithin Formula VI consists of divalent radicals wherein each of R²¹⁴ andR²¹⁵ is hydrido; wherein each of R²¹⁶ and R²¹⁷ is independently selectedfrom hydrido and alkyl; and wherein p is two. A specific example of amore preferred linker within Formula VI is the divalent radicalethylenediamino. In Table III there is shown a class of specificexamples of diamino-terminated linker groups within Formula VI. Theselinker groups, identified as Linker Nos. 96-134, would be suitable toform a conjugate between a carbonyl moiety of an AII antagonist(designated as "I") and a carbonyl moiety of carbonyl terminated secondresidue such as the carbonyl moiety attached to the gamma carbon of aglutamyl residue (designated as "T").

                                      TABLE III                                   __________________________________________________________________________     ##STR56##                                                                    I = inhibitor                                                                 G = acetyl-γ-glutamyl                                                   LINKER                                                                        NO.   R.sup.218                                                                          R.sup.219                                                                          R.sup.220                                                                           R.sup.221                                                                          R.sup.222                                                                          R.sup.223                                     __________________________________________________________________________     96   H    H    H     H    H    H                                              97   H    H    H     H    H    CH.sub.3                                       98   H    H    H     CH.sub.3                                                                           H    H                                              99   H    H    H     CH.sub.3                                                                           H    CH.sub.3                                      100   CH.sub.3                                                                           H    H     H    H    H                                             101   H    CH.sub.3                                                                           H     H    H    H                                             102   H    H    H     H    CH.sub.3                                                                           CH.sub.3                                      103   H    H    CH.sub.3                                                                            CH.sub.3                                                                           H    H                                             104   CH.sub.3                                                                           CH.sub.3                                                                           H     H    H    H                                             105   H    H    H     H    H    C.sub.6 H.sub.5                               106   H    H    H     C.sub.6 H.sub.5                                                                    H    H                                             107   H    H    H     C.sub.6 H.sub.5                                                                    H    C.sub.6 H.sub.5                               108   C.sub.6 H.sub.5                                                                    H    H     H    H    H                                             109   H    C.sub.6 H.sub.5                                                                    H     H    H    H                                             110   H    H    H     H    C.sub.6 H.sub.5                                                                    C.sub.6 H.sub.5                               111   H    H    C.sub.6 H.sub.5                                                                     C.sub.6 H.sub.5                                                                    H    H                                             112   C.sub.6 H.sub.5                                                                    C.sub.6 H.sub.5                                                                    H     H    H    H                                             113   H    H    H     H    H    C.sub.2 H.sub.5                               114   H    H    H     C.sub.2 H.sub.5                                                                    H    H                                             115   H    H    H     C.sub.2 H.sub.5                                                                    H    C.sub.2 H.sub.5                               116   C.sub.2 H.sub.5                                                                    H    H     H    H    H                                             117   H    C.sub.2 H.sub.5                                                                    H     H    H    H                                             118   H    H    H     H    C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                               119   H    H    C.sub.2 H.sub.5                                                                     C.sub.2 H.sub.5                                                                    H    H                                             120   C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                    H     H    H    H                                             121   CH.sub.3                                                                           H    C.sub.6 H.sub.5                                                                     H    H    H                                             122   CH.sub.3                                                                           H    H     H    C.sub.6 H.sub.5                                                                    H                                             123   H    CH.sub.3                                                                           C.sub.6 H.sub.5                                                                     H    H    H                                             124   H    CH.sub.3                                                                           H     H    C.sub.6 H.sub.5                                                                    H                                             125   CH.sub.3                                                                           CH.sub.3                                                                           H     C.sub.6 H.sub.5                                                                    H    H                                             126   CH.sub.3                                                                           CH.sub.3                                                                           H     H    H    C.sub.6 H.sub.5                               127   H    H    H     H    H    CH.sub.2 C.sub.6 H.sub.5                      128   H    H    H     CH.sub.2 C.sub.6 H.sub.5                                                           H    H                                             129   CH.sub.2 C.sub.6 H.sub.5                                                           H    H     H    H    H                                             130   H    CH.sub.2 C.sub.6 H.sub.5                                                           H     H    H    H                                             131   CH.sub.3                                                                           H    CH.sub.2 C.sub.6 H.sub.5                                                            H    H    H                                             132   CH.sub.3                                                                           H    H     H    CH.sub.2 C.sub.6 H.sub.5                                                           H                                             133   H    CH.sub.3                                                                           CH.sub.2 C.sub.6 H.sub.5                                                            H    H    H                                             134   H    CH.sub.3                                                                           H     H    CH.sub.2 C.sub.6 H.sub.5                                                           H                                             __________________________________________________________________________

The term "hydrido" denotes a single hydrogen atom (H) which may beattached, for example, to a carbon atom to form a hydrocarbyl group orattached to an oxygen atom to form an hydroxyl group. Where the term"alkyl" is used, either alone or within other terms such as "haloalkyl"and "hydroxyalkyl", the term "alkyl" embraces linear or branchedradicals having one to about twenty carbon atoms or, preferably, one toabout twelve carbon atoms. More preferred alkyl radicals are "loweralkyl" radicals having one to about ten carbon atoms. Most preferred arelower alkyl radicals having one to about five carbon atomms. The term"cycloalkyl" embraces cyclic radicals having three to about ten ringcarbon atoms, preferably three to about six carbon atoms, such ascyclopropyl and cyclobutyl. The term "haloalkyl" embraces radicalswherein any one or more of the alkyl carbon atoms is substituted withone or more halo groups, preferably selected from bromo, chloro andfluoro. Specifically embraced by the term "haloalkyl" are monohaloalkyl,dihaloalkyl and polyhaloalkyl groups. A monohaloalkyl group, forexample, may have either a bromo, a chloro, or a fluoro atom within thegroup. Dihaloalkyl and polyhaloalkyl groups may be substituted with twoor more of the same halo groups, or may have a combination of differenthalo groups. A dihaloalkyl group, for example, may have two fluoroatoms, such as difluoromethyl and difluorobutyl groups, or two chloroatoms, such as a dichloromethyl group, or one fluoro atom and one chloroatom, such as a fluoro-chloromethyl group. Examples of a polyhaloalkylare trifluoromethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl,perfluoroethyl and 2,2,3,3-tetrafluoropropyl groups. The term"difluoroalkyl" embraces alkyl groups having two fluoro atomssubstituted on any one or two of the alkyl group carbon atoms.Preferably, when the difluoroalkyl group is attached at the triazolering R¹ and R² positions of Formula I, the two fluoro atoms aresubstituted on the carbon atom which is attached directly to thetriazole ring. Such preferred difluoroalkyl group may be characterizedas an "alpha-carbon difluoro-substituted difluoroalkyl group". The terms"alkylol" and "hydroxyalkyl" embrace linear or branched alkyl groupshaving one to about ten carbon atoms any one of which may be substitutedwith one or more hydroxyl groups. The term "alkenyl" embraces linear orbranched radicals having two to about twenty carbon atoms, preferablythree to about ten carbon atoms, and containing at least onecarbon-carbon double bond, which carbon-carbon double bond may haveeither cis or trans geometry within the alkenyl moiety. The term"alkynyl" embraces linear or branched radicals having two to abouttwenty carbon atoms, preferably two to about ten carbon atoms, andcontaining at least one carbon-carbon triple bond. The term"cycloalkenyl" embraces cyclic radicals having three to about ten ringcarbon atoms including one or more double bonds involving adjacent ringcarbons. The terms "alkoxy" and "alkoxyalkyl" embrace linear or branchedoxy-containing radicals each having alkyl portions of one to about tencarbon atoms, such as methoxy group. The term "alkoxyalkyl" alsoembraces alkyl radicals having two or more alkoxy groups attached to thealkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkylgroups. The "alkoxy" or "alkoxyalkyl" radicals may be furthersubstituted with one or more halo atoms, such as fluoro, chloro orbromo, to provide haloalkoxy or haloalkoxyalkyl groups. The term"alkylthio" embraces radicals containing a linear or branched alkylgroup, of one to about ten carbon atoms attached to a divalent sulfuratom, such as a methythio group. The term "aryl" embraces aromaticradicals such as phenyl, naphthyl and biphenyl. The term "aralkyl"embraces aryl-substituted alkyl radicals such as benzyl, diphenylmethyl,triphenylmethyl, phenylethyl, phenylbutyl and diphenylethyl. The terms"benzyl" and "phenylmethyl" are interchangeable. The terms "aryloxy" and"arylthio" denote radical respectively, aryl groups having an oxygen orsulfur atom through which the radical is attached to a nucleus, examplesof which are phenoxy and phenylthio. The terms "sulfinyl" and"sulfonyl", whether used alone or linked to other terms, denotesrespectively divalent radicals SO and SO₂. The term "aralkoxy", alone orwithin another term, embraces an aryl group attached to an alkoxy groupto form, for example, benzyloxy. The term "acyl" whether used alone, orwithin a term such as acyloxy, denotes a radical provided by the residueafter removal of hydroxyl from an organic acid, examples of such radicalbeing acetyl and benzoyl. The term "heteroaryl" embraces aromatic ringsystems containing one or two hetero atoms selected from oxygen,nitrogen and sulfur in a ring system having five or six ring members,examples of which are thienyl, furanyl, pyridinyl, thiazolyl, pyrimidyland isoxazolyl. Such heteroaryl may be attached as a substituent througha carbon atom of the heteroaryl ring system, or may be attached througha carbon atom of a moiety substituted on a heteroaryl ring-member carbonatom, for example, through the methylene substituent of imidazolemethylmoiety. Also, such heteroaryl may be attached through a ring nitrogenatom as long as aromaticity of the heteroaryl moiety is preserved afterattachment.

Specific examples of alkyl groups are methyl, ethyl, n-propyl,isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl,isopentyl, methylbutyl, dimethylbutyl and neopentyl. Typical alkenyl andalkynyl groups may have one unsaturated bond, such as an allyl group, ormay have a plurality or unsaturated bonds, with such plurality of bondseither adjacent, such as allene-type structures, or in conjugation, orseparated by several saturated carbons.

Conjugates of the invention formed from compounds of Formula I have beenfound to inhibit the action of angiotensin II in mammals. For example,specific biphenylmethyl 1H-substituted-imidazole compounds withinFormula I have been evaluated for angiotensin II receptor binding andantihypertensive effects in renal hypertensive rats, as shown in EP#253,310 published Jan. 20, 1988. Thus, conjugates of Formula I aretherapeutically useful in methods for treating hypertension byadministering to a hypertensive patient a therapeutically-effectiveamount of a conjugate containing a compound of Formula I, such that theconjugate is hydrolyzed by an enzyme found predominantly in the kidneyso as to release an active angiotensin II antagonist species. The phrase"hypertensive patient" means, in this context, a mammalian subjectsuffering from the effects of hypertension or susceptible to ahypertensive condition if not treated to prevent or control suchhypertension.

Included within the invention are conjugates of compounds of Formula Iwhich are tautomeric forms of the described compounds, isomeric formsincluding diastereoisomers, and the pharmaceutically-acceptable saltsthereof. The term "pharmaceutically-acceptable salts" embraces saltscommonly used to form alkali metal salts and to form addition salts offree acids or free bases. The nature of the salt is not critical,provided that it is pharmaceutically-acceptable. Suitablepharmaceutically-acceptable acid addition salts of compounds of FormulaI may be prepared from an inorganic acid or from an organic acid.Examples of such inorganic acids are hydrochloric, hydrobromic,hydroiodic, nitric, carbonic, suffuric and phosphoric acid. Appropriateorganic acids may be selected from aliphatic, cycloaliphatic, aromatic,araliphatic, heterocyclic, carboxylic and sulfonic classes of organicacids, example of which are formic, acetic, propionic, succinic,glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic,glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic,anthranilic, p-hydroxybenzoic, salicyclic, phenylacetic, mandelic,embonic (pamoic), methansulfonic, ethanesulfonic,2-hydroxyethanesulfonic, pantothenic, benzenesulfonic, toluenesulfonic,sulfanilic, mesylic, cyclohexylaminosulfonic, stearic, algenic,β-hydroxy butyric, malonic, galactaric and galacturonic acid. Suitablepharmaceutically-acceptable base addition salts of compounds of FormulaI include metallic salts made from aluminium, calcium, lithium,magnesium, potassium, sodium and zinc or organic salts made fromN,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine (N-methylglucamine) and procaine. All ofthese salts may be prepared by conventional means from the correspondingcompound of Formula I by reacting, for example, the appropriate acid orbase with the compound of Formula I. Also, such pharmaceutical salts maybe formed with either a compound of Formula I which is contained in theconjugate, or such salts may be formed with the conjugate itself.

Conjugates of the invention can possess one or more asymmetric carbonatoms and are thus capable of existing in the form of optical isomers aswell as in the form of racemic or non-racemic mixtures thereof. Theoptical isomers can be obtained by resolution of the racemic mixturesaccording to conventional processes, for example by formation ofdiastereoisomeric salts by treatment with an optically active acid orbase. Examples of appropriate acids are tartaric, diacetyltartaric,dibenzoyltartaric, ditoluoyltartaric and camphorsulfonic acid and thenseparation of the mixture of diastereoisomers by crystallizationfollowed by liberation of the optically active bases from these salts. Adifferent process for separation of optical isomers involves the use ofa chiral chromatography column optimally chosen to maximize theseparation of the enantiomers. Still another available method involvessynthesis of covalent diastereoisomeric molecules by reacting conjugateswith an optically pure acid in an activated form or an optically pureisocyanate. The synthesized diastereoisomers can be separated byconventional means such as chromatography, distillation, crystallizationor sublimation, and then hydrolyzed to deliver the enantiomerically purecompound. The optically active conjugates can likewise be obtained byutilizing optically active starting materials. These isomers may be inthe form of a free acid, a free base, an ester or a salt.

Conjugates of the invention may be prepared using precursors of highlyactive angiotensin II antagonists of Formula I. Examples of lesseractive, suitable precursors are acid chloride, esters and amides ofangiotensin II antagonists of Formula I. For example, ester precursorsof angiotensin II antagonists, such as the methyl ester precursor madein Step 1 of Example 81, may be reacted with hydrazine to provide anamino terminal moiety which then can be reacted with a glutamic acidderivative to form a conjugate of the invention. Such precursors orintermediates themselves may be relatively strong, relatively weak, orinactive as AII antagonists. Also, conjugates of the invention may beprepared using angiotensin II antagonists lacking a reactive terminalamino moiety. Such angiotensin II antagonists, as shown in Example Nos.78-80 of Table IV, lack a terminal amino moiety. These AII antagonistcompounds may be modified as described in Example Nos. 711 and 712 tocontain a terminal acid moiety which then may be connected to a glutamylresidue through a diamino-terminated linker group, such as shown inTables I-III.

Synthetic Procedures

Conjugates of the invention are synthesized by reaction betweenprecursors of the first and second residues. One of such precursors mustcontain a reactive acid moiety, and the other precursor must contain areactive amino moiety, so that a conjugate is formed having a cleavablebond. Either precursor of the first and second residues may contain suchreactive acid or amino moieties. Preferably, the precursors of the firstresidue are angiotensin II antagonists and will contain a reactive aminomoiety or a moiety convertible to a reactive amino moiety. Inhibitorcompounds lacking a reactive amino moiety may be chemically modified toprovide such reactive amino moiety. Chemical modification of theseinhibitor compounds lacking a reactive amino group may be accomplishedby reacting an acid or an ester group on an AII antagonist compound withan amino compound having at least one reactive amino moiety. A suitableamino compound would be a diamino compound such as hydrazine, urea orethylenediamine. Hydrazine, for example, may be reacted with acarboxylic acid or ester moiety of an AII antagonist compound to form ahydrazide derivative of such AII antagonist compound.

In the following general Synthetic Procedures, there is describedfirstly in Scheme I, methods for making suitable angiotensin IIantagonists of Formula I for selection as the first component of theconjugate. Then, in Schemes II-VII, there are described general methodsfor making a conjugate by reacting a first component AII antagonist ofFormula I with a cleavable second component represented byN-acetyl-γ-glutamic acid. ##STR57##

Synthetic Scheme I shows the coupling reaction of trisubstitutedimidazoles 1 with the appropriate alkylating reagent 2. In the firststep, 1 and 2 are reacted in dimethylformaide (DMF) in the presence ofbase, such as cesium carbonate, and a dehydrating agent, such asmolecular seives, to give a mixture of coupled regioisomers 3a and 3b.The isomer mixture may be converted to mixtures of the correspondingacids 4a and 4b or tetrazoles 5a and 5b. Or, the isomers 3a and 3b maybe separated by chromatographic methods, and each isomer may be reactedwith the appropriate reagent to provide the acid- ortetrazole-substituted end product. ##STR58##

Synthetic Scheme II shows the preparation of the renal-selectiveangiotensin II antagonists by coupling γ-glutamic acid with one of theangiotensin II antagonist regiosiomers 3a (the synthesis of the otherregioisomer is shown in Scheme III); the biphenyl R⁵ acid moiety of theAII antagonist is coupled to the γ-acid moiety of glutamic acid via anhydrazine linker. In step 1, the methyl ester of the AII antagonist 3ais converted to the hydrazide 6a by the action of hydrazine. In step 2,the hydrazide 6a is first reacted with the symmetrical anhydride of theprotected γ-glutamic acid 7 and subsequently reacted withtrifluoroacetic acid (TFA) to give the deprotected coupled material 8a.In Step 3, the free amino group of 8a is acetylated with aceticanhydride in the presence of base to give the renal-selectiveangiotensin II antagonist 9a. ##STR59##

Synthetic Scheme III shows the preparation of renal-selectiveangiotensin II antagonists by coupling γ-glutamic acid with one of theangiotensin II antagonist regioisomers 3b (the synthesis of the otherregioisomer is shown in Scheme II); the biphenyl R⁵ acid moiety of theAII antagonist is coupled to the γ-acid moiety of glutamic acid via anhydrazine linker. In step 1, the methyl ester of the AII antagonist 3bis converted to the hydrazide 6b by the action of hydrazine. In step 2,the hydrazide 6b is first reacted with the symmetrical anhydride of theprotected γ-glutamic acid 7 and subsequently reacted with TFA to givethe deprotected coupled material 8b. In step 3, the free amino group of8b is acetylated with acetic anhydride in the presence of base to givethe renal-selective angiotensin II antagonist 9b. ##STR60##

Synthetic Scheme IV shows the preparation of renal-selective angiotensinII antagonists by coupling γ-glutamic acid with one of the angiotensinII antagonist regiosiomers 3a which contains an amino moiety in theimidazole R¹ group (the synthesis of the other regioisomer is shown inScheme V). In step 1, the AII antagonist 3a is reacted with thesymmetrical anhydride of the protected γ-glutamic acid 7 to give 10a. Instep 2, the protected material 10a is reacted with TFA to give thedeprotected coupled material 11a. In step 3, the free amino compound 11ais acetylated with acetic anhydride in the presence of base to give therenal-selective angiotensin II antagonist 12b. ##STR61##

Synthetic Scheme V shows the preparation of renal-selective angiotensinII antagonists by coupling γ-glutamic acid with one of the angiotensinII antagonist regioisomers 3b which contains an amino moiety in theimidazole R¹ group (the synthesis of the other regioisomer is shown inScheme IV). In step 1, the AII antagonit 3b is reacted with thesymmetrical anhydride of the protected γ-glutamic acid 7 to give 10b. Instep 2, the protected material 10b is reacted with TFA to give thedeprotected coupled material 11b. In step 3, the free amino compound 11bis acetylated with acetic anhydride in the presence of base to give therenal-selective angiotensin II antagonist 12b. ##STR62##

Synthetic Scheme VI shows the preparation of renal-selective angiotensinII antagonists by coupling γ-glutamic acid with one of the angiotensinII antagonist regioisomers 3a which contains an acid moiety in theimidazole R¹ group (the synthesis of the other regioisomer is shown inScheme VII); the imidazole R¹ acid moiety of the AII antagonist iscoupled to the γ-acid moiety of glutamic acid via an hydrazine linker.In step 1, the methyl ester of the AII antagonist 3a is converted to thehydrazide 13a by the action of hydrazine. In step 2, the hydrazide 13ais first reacted with the symmetrical anhydride of the protectedγ-glutamic acid 7 and subsequently reacted with TFA to give thedeprotected coupled material 14a. In step 3, the free amino group of 14ais acetylated with acetic anhydride in the presence of base to give therenal-selective angiotensin II antagonist 15a. ##STR63##

Synthetic Scheme VII shows the preparation of renal-selectiveangiotensin II antagonists by coupling γ-glutamic acid with one of theangiotensin II antagonist regioisomers 3b which contains an acid moietyin the imidazole R¹ group (the synthesis of the other isomer is shown inScheme VII); the imidazole R¹ acid moiety of the AII antagonist iscoupled to the γ-acid moiety of glutamic acid via an hydrazine linker.In step 1, the methyl ester of the AII antagonist 3b is converted to thehydrazide 13b by the action of hydrazine. In step 2, the hydrazide 13bis first reacted with the symmetrical anhydride of the protectedγ-glutamic acid 7 and subsequently reacted with TFA to give thedeprotected coupled material 14b. In step 3, the free amino group of 14bis acetylated with acetic anhydride in the presence of base to give therenal-selective angiotensin II antagonist 15b.

The following Examples 1-80 shown in Table IV are angiotensin IIantagonists suitable for selection as precursors to provide the firstresidue of a conjugate of the invention. These angiotensin IIantagonists may be prepared generally by the procedures outlined abovein Scheme I. Also, specific procedures for preparation of Examples 1-80of Table IV may be found in EP #253,310 published Jan. 20, 1988.

                                      TABLE IV                                    __________________________________________________________________________     ##STR64##                                                                    Ex. #                                                                             R.sup.0      R.sup.2          R.sup.1                                                                            R.sup.5                                __________________________________________________________________________     1  C.sub.4 H.sub.9 (n)                                                                        CH.sub.2 OCOCH.sub.3                                                                           Cl   CO.sub.2 H                              2  C.sub.4 H.sub.9 (n)                                                                        CH.sub.2 OH      NO.sub.2                                                                           CO.sub.2 H                              3  C.sub.4 H.sub.9 (n)                                                                        CH.sub.2 OH      CF.sub.3                                                                           CO.sub.2 H                              4  SC.sub.3 H.sub.7                                                                           CH.sub.2 OH      H    CO.sub.2 H                              5  C.sub.4 H.sub.9 (n)                                                                        CH.sub.2 OH      Cl   CO.sub.2 H                              6  C.sub.4 H.sub.9 (n)                                                                        Cl               CH.sub.2 OH                                                                        CO.sub.2 H                              7  C.sub.4 H.sub.9 (n)                                                                        H                CH.sub.2 OH                                                                        CO.sub.2 H                              8  C.sub.4 H.sub.9 (n)                                                                        CH.sub.2 OH      H    CO.sub.2 H                              9  C.sub.4 H.sub.9 (n)                                                                        CH.sub.2 OCH.sub.3                                                                             Cl   CO.sub.2 H                             10  C.sub.4 H.sub.9 (n)                                                                        CH.sub.2 OCH(CH.sub.3).sub.2                                                                   Cl   CO.sub.2 H                             11  C.sub.4 H.sub.9 (n)                                                                        CH.sub.2 OH      Br   CO.sub.2 H                             12  C.sub.4 H.sub.9 (n)                                                                        CH.sub.2 OH      F    CO.sub.2 H                             13  C.sub.4 H.sub.9 (n)                                                                        CH.sub.2 OH      I    CO.sub.2 H                             14                                                                                 ##STR65##   CH.sub.2 OH      Cl   CO.sub.2 H                             15                                                                                 ##STR66##   CH.sub.2 OH      Cl   CO.sub.2 H                             16  C.sub.4 H.sub.9 (n)                                                                        I                CH.sub.2 OH                                                                        CO.sub.2 H                             17  C.sub.3 H.sub.7 (n)                                                                        CH.sub.2 OH      Cl   CO.sub.2 H                             18  C.sub.2 H.sub.5                                                                            CH.sub.2 OH      Cl   CO.sub.2 H                             19  C.sub.3 H.sub.7 (n)                                                                        CH.sub.2 OH      Cl   CO.sub.2 H                             20  C.sub.5 H.sub.11 (n)                                                                       CH.sub.2 OH      Cl   CO.sub.2 H                             21  C.sub.6 H.sub.13 (n)                                                                       CH.sub.2 OH      Cl   CO.sub.2 H                             22  C.sub.4 H.sub.9 (n)                                                                        CH.sub.2 SH      Cl   CO.sub.2 H                             23  C.sub.4 H.sub.9 (n)                                                                        CH.sub.2 OC.sub.6 H.sub.5                                                                      Cl   CO.sub.2 H                             24  C.sub. 3 H.sub.7 (n)                                                                       CHO              Cl   CO.sub.2 H                             25  C.sub.4 H.sub.9 (n)                                                                        CH.sub.2 CO.sub.2 H                                                                            Cl   CO.sub.2 H                             26  C.sub.4 H.sub.9 (n)                                                                        CH(CH.sub.3)CO.sub.2 H                                                                         Cl   CO.sub.2 H                             27  C.sub.4 H.sub.9 (n)                                                                        NO.sub.2         CH.sub.2 OH                                                                        CO.sub.2 H                             28  C.sub.4 H.sub.9 (n)                                                                        CH.sub.2 OCOCH.sub.3                                                                           Cl   CO.sub.2 H                             29  C.sub.4 H.sub.9 (n)                                                                         ##STR67##       Cl   CO.sub.2 H                             30  SC.sub.4 H.sub.9 (n)                                                                       CH.sub.2 OH      H    CO.sub.2 H                             31                                                                                 ##STR68##   CH.sub.2 OH      H    CO.sub.2 H                             32  C.sub.4 H.sub.9 (n)                                                                        CHO              Cl   CO.sub.2 H                             33  C.sub.4 H.sub.9 (n)                                                                        CO.sub.2 CH.sub.3                                                                              Cl   CO.sub.2 H                             34  C.sub.4 H.sub.9 (n)                                                                        CONH.sub.2       Cl   CO.sub.2 H                             35                                                                                 ##STR69##   CH.sub.2 OH      Cl   CO.sub.2 H                             36                                                                                 ##STR70##   CHO              Cl   CO.sub.2 H                             37  C.sub.4 H.sub.9 (n)                                                                        CHO              H    CO.sub.2 H                             38  C.sub.4 H.sub. 9 (n)                                                                       CHO              CF.sub.3                                                                           CO.sub.2 H                             39  C.sub.4 H.sub.9 (n)                                                                        CONHCH.sub.3     Cl   CO.sub.2 H                             40  C.sub.4 H.sub.9 (n)                                                                        CON(CH.sub.3).sub.2                                                                            Cl   CO.sub.2 H                             41                                                                                 ##STR71##   CH.sub.2 OH      Cl   CO.sub.2 H                             42                                                                                 ##STR72##   CH.sub.2 OH      CF.sub.3                                                                           CO.sub.2 H                             43                                                                                 ##STR73##   CHO              Cl   CO2H                                   44  C.sub.4 H.sub.9 (n)                                                                         ##STR74##       Cl   CO.sub.2 H                             45  C.sub.4 H.sub.9 (n)                                                                         ##STR75##       Cl   CO.sub.2 H                             46  C.sub.4 H.sub.9 (n)                                                                        CH.sub.2 NHCO.sub.2 CH.sub.3                                                                   Cl   CO.sub.2 H                             47  C.sub.4 H.sub.9 (n)                                                                        CH.sub.2 NHCO.sub.2 C.sub.3 H.sub.7                                                            Cl   CO.sub.2 H                             48  C.sub.4 H.sub.9 (n)                                                                        CH.sub.2 NHCO.sub.2 CH.sub.2 (CH.sub.3).sub.2                                                  Cl   CO.sub.2 H                             49  C.sub.4 H.sub.9 (n)                                                                        CH.sub.2 NHCO.sub.2 C.sub.4 H.sub.9                                                            Cl   CO.sub.2 H                             50  C.sub.4 H.sub.9 (n)                                                                        CH.sub.2 NHCO.sub. 2 -adamantyl                                                                Cl   CO.sub.2 H                             51  C.sub.3 H.sub.7 (n)                                                                        CH.sub.2 NHCO.sub.2 CH.sub.3                                                                   Cl   CO.sub.2 H                             52  C.sub.4 H.sub.9 (n)                                                                        CH.sub.2 NHCO.sub.2 CH.sub.3                                                                   Cl   CO.sub.2 H                             53  C.sub.4 H.sub.9 (n)                                                                        CH.sub.2 NHCO.sub.2 C.sub.2 H.sub.5                                                            Cl   CO.sub.2 H                             54  C.sub.4 H.sub.9 (n)                                                                        CH.sub.2 NHCO.sub.2 C.sub.3 H.sub.7                                                            Cl   CO.sub.2 H                             55  C.sub.4 H.sub.9 (n)                                                                        CH.sub.2 NHCO.sub.2 C.sub.4 H.sub.9                                                            Cl   CO.sub.2 H                             56  C.sub.4 H.sub.9 (n)                                                                        CH.sub.2 NHCO.sub.2 CH(CH.sub.3).sub.2                                                         Cl   CO.sub.2 H                             57  C.sub.4 H.sub.9 (n)                                                                        CH.sub.2 NHCO.sub.2 (1-naphthyl)                                                               Cl   CO.sub.2 H                             58  C.sub.4 H.sub.9 (n)                                                                        CH.sub.2 NHCONHCH.sub.3                                                                        Cl   CO.sub.2 H                             59  C.sub.4 H.sub.9 (n)                                                                        CH.sub.2 NHCONHC.sub.2 H.sub.5                                                                 Cl   CO.sub.2 H                             60  C.sub.4 H.sub.9 (n)                                                                        CH.sub.2 NHCONHC.sub.3 H.sub.7                                                                 Cl   CO.sub.2 H                             61  C.sub.4 H.sub.9 (n)                                                                        CH.sub.2 NHCONHC.sub.4 H.sub.9                                                                 Cl   CO.sub.2 H                             62  C.sub.4 H.sub.9 (n)                                                                        CH.sub.2 NHCONHCH(CH.sub.3).sub.2                                                              Cl   CO.sub.2 H                             63  C.sub.4 H.sub.9 (n)                                                                        CH.sub.2 NHCONH(1-napthyl)                                                                     Cl   CO.sub.2 H                             64  C.sub.3 H.sub.7 (n)                                                                         ##STR76##       H    CO.sub.2 H                             65  C.sub.3 H.sub.7 (n)                                                                         ##STR77##       Cl   CO.sub.2 H                             66  C.sub.3 H.sub.7 (n)                                                                         ##STR78##       Cl   CO.sub.2 H                             67  C.sub.4 H.sub.9 (n)                                                                         ##STR79##       Cl   CO.sub.2 H                             68  C.sub.4 H.sub.9 (n)                                                                        CH.sub.2 CH.sub.2 CO.sub.2 H                                                                   Cl   CO.sub.2 H                             69  C.sub.4 H.sub.9 (n)                                                                        CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CO.sub.2 H                                                 Cl   CO.sub.2 H                             70                                                                                 ##STR80##   CH.sub.2 OH      Cl   CO.sub.2 H                             71  C.sub.4 H.sub.9 (n)                                                                         ##STR81##       Cl   CO.sub. 2 H                            72  C.sub.4 H.sub.9 (n)                                                                         ##STR82##       Cl   CO.sub.2 H                             73  C.sub.4 H.sub.9 (n)                                                                         ##STR83##       H    CO.sub.2 H                             74  C.sub.4 H.sub.9 (n)                                                                         ##STR84##       H    CO.sub.2 H                             75  C.sub.4 H.sub.9 (n)                                                                        CH.sub.2 CH.sub.2 CH.sub.2 F                                                                   Cl   CO.sub.2 H                             76  C.sub.4 H.sub.9 (n)                                                                        CH.sub.2 ONO.sub.2                                                                             Cl   CO.sub.2 H                             77  C.sub.4 H.sub.9 (n)                                                                        CH.sub.2                                                                          ##STR85##    Cl   CO.sub.2 H                             78  C.sub.4 H.sub.9 (n)                                                                        CH.sub.2 OH      Cl   CN.sub.4 H                             79  C.sub.4 H.sub.9 (n)                                                                        Cl               CH.sub.2 OH                                                                        CN.sub.4 H                             80  C.sub.4 H.sub.9 (n)                                                                        CHO              Cl   CN.sub.4 H                             __________________________________________________________________________

A class of highly preferred specific conjugates of the invention isprovided by conjugates formed from a biphenylmethyl 1H-substitutedimidazole AII antagonist compound linked to a cleavable glutamylresidue. Each conjugate contains a diamino linker moiety which connectsa terminal carboxylic acid moiety on the biphenylmethyl portion of theAII antagonist compound with a terminal carboxylic acid moiety on thegamma carbon of the cleavable glutamyl residue. Such conjugates areshown herein as Examples 81-146. General procedures for preparation ofthe conjugates of Examples 81-146 are described in Schemes II-III.Detailed procedures for preparation of representative conjugates aredescribed in Examples 81 and 82. Similar procedures may be used forpreparation of the conjugates identified as Examples 83-146 shown inTable V.

EXAMPLE 81 ##STR86## N-acetyl-L-glutamic acid,5-[[4'-[2-butyl-4-chloro-5-(hydroxymethyl)-1H-imidazol-1-ylmethyl][1,1'-biphenyl]-2-yl]carbonyl]hydrazideStep 1: Preparation of1-(2'-methoxycarbonyl-biphenyl-4-yl)methyl]-2-butyl-4-chloro-5-hydroxymethylimidazole.

Under nitrogen, a solution of 6.69 g (36 mmol) of2-butyl-4-chloro-5-hydroxymethylimidazole in 100 mL of anhydrousdimethylformamide (DMF) was treated with molecular seives and 11.0 g (36mmol) of 4-bromomethyl-2'-methoxycarbonylbiphenyl. The reaction wasallowed to stir at ambient temperature overnight and then was filtered.The DMF was removed in vacuo and the residue was partitioned betweenwater and chloroform; the chloroform extracts were combined, dried(MgSO₄), and concentrated in vacuo giving 17.4 g of crude material.Purification by silica gel chromatography (Waters Prep-500A) using ethylacetate/hexane (40:60) gave the 4-hydroxymethyl isomer as theregioisomer with the lower Rf value and 6.27 g (42%) of the5-hydroxymethyl isomer: NMR (CDCl₃) δ 0.91 (t, J=7 Hz, 3H), 1.29-1.44(m, 2H), 1.52 (t, J=8 Hz, 1H), 1.63-1.76 (m, 2H), 2.62 (t, J=7 Hz, 2H),3.65 (s, 3H), 4.54 (d, J=8 Hz, 2H), 7.02-7.08 (m, 2H), 7.25-7.36 (m,3H), 7.38-7.47 (m, 1H), 7.50-7.58 (m, 1H), 7.83-7.90 (m, 1H).

Step 2: Preparation of1-[(2'-hydrazinylcarbonyl-biphenyl-4-yl)methyl]-2-butyl-4-chloro-5-hydroxymethylimidazole.

Under nitrogen, 6.27 g (15 mmol) of the 5-hydroxymethyl ester from step1 was dissolved in 100 mL of methanol and treated with 15 mL (480 mmol)of anhydrous hydrazine. The reaction was allowed to stir at refluxovernight; concentration in vacuo gave 4.83 g of crude material.Purification by silica gel chromatography (Waters Prep-500A) usingisopropanol/ethyl acetate (20:80) gave 4.27 g (68%) of the hydrazide asa colorless glass: NMR (CDCl₃) δ 0.81 (t, J=7 Hz, 3H), 1.18-1.34 (m,2H), 1.42-1.56 (m, 2H), 2.50 (t, J=Hz, 2H), 4.15-4.35 (br s, 2H), 4.35(d, J=8 Hz, 2H), 5.24 (t, J=8 Hz, 1H), 7.05-7.13 (m, 2H), 7.32-7.44 (m,5H), 7.45-7.54 (m, 1H), 9.34 (s, 1H).

Step 3: Preparation of N-acetyl-L-glutamic acid,5-[[4'-2-butyl-4-chloro-5-(hydroxymethyl)-1H-imidazol-1-ylmethy][1,1'-biphenyl]-2-yl]carbonyl]hydrazide.

To a solution of 1.70 g (5.60 mmol) of N-Boc-L-glutamic acid-α-tertbutylester (BACHEM) in 50 mL of methylene chloride under nitrogen was added580 mg (2.8 mmol) of solid dicyclohexylcarbodiimide (DCC). The reactionwas allowed to stir for 2 h and filtered under nitrogen. The anhydridesolution was then added to a solution of 1.0 g (2.4 mmol) of hydrazidefrom step 2 in 75 mL of methylene chloride under nitrogen. The reactionwas stirred overnight, concentrated to a volume of 25 mL, cooled to 0°C., and treated with 25 mL of TFA under nitrogen. The stirred reactionwas allowed to warm to ambient temperature overnight and concentrated invacuo. The crude product wad dissolved in 100 mL of acetonitrile/water(1:1) and the pH adjusted to 8 with 1M K₂ CO₃. The solution was cooledto 0° and 0.23 mL (2.4 mmol) of acetic anhydride and 2.4 mL (2.4 mmol)of 1M K₂ CO₃ was added every 30 min for 5 h; the pH was maintained at 9and the reaction temperature kept below 5° C. After the last addition,the reaction was allowed to warm to ambient temperature overnight. ThepH was adjusted to 4 with 3M HCl and the reaction was concentrated to100 mL. Purification by reverse phase chromatography (WatersDeltaprep-3000) using isocratic 25% acetonitrile/water (0.05% TFA) gave1.0 g 75% overall yield from the hydrazide of step 2) of colorlessproduct: NMR (DMSO-d₆) δ 0.81 (t, J=7Hz, 3H), 1.20-1.30 (m, 2H),1.42-1.55 (m, 2H), 1.75-1.84 (m, 2H), 1.85 (s, 3H), 1.89-2.05 (m, 2H),2.21 (t, J=7Hz, 2H), 4.13-4.24 (m, 1H), 4.35 (s, 2 H), 7.05-7.12 (m,2H), 7.37-7.58 (m, 6H), 8.12-8.17 (m, 2H); MS (FAB) m/e (rel. intensity)584 (18), 568 (100), 225 (64); HRMS. Calcd for M+H: 584.2276. Found:584.2240.

EXAMPLE 82 ##STR87## N-acetyl-L-glutamic acid,5-[[4'-[2-butyl-5-chloro-4-(hydroxymethyl)-1H-imidazol-1-ylmethyl][1,1'-biphenyl]-2-yl]carbonyl]hydrazideStep 1: Preparation of1-[(2'-hydrazinylcarbonyl-biphenyl-4-yl)methyl]-2-butyl-5-chloro-4-hydroxymethylimidazole.

Under nitrogen, 4.13 g (10 mmol) of the 4-hydroxymethyl ester from step1 of Example 81 is dissolved in 100 mL of methanol and is treated with15 mL of (480 mmol) of anhydrous hydrazine. The reaction is allowed tostir at reflux overnight; concentration in vacuo gives the crudematerial. Purification by silica gel chromatography (Waters Prep-500A)gives the pure hydrazide.

Step 2: Preparation of N-acetyl-L-glutamic acid.5-[[4'-2-butyl-5-chloro-4-(hydroxymethyl)-1H-imidazol-1-ylmethyl][1,1'-biphenyl]-2-yl]carbonyl]hydrazide

To a solution of 1.70 g (5.6 mmol) of N-Boc-L-glutamic acid-o-tertbutylester (BACHEM) in 50 mL of methylene chloride under nitrogen is added580 mg (2.8 mmol) of solid dicylcohexylcarbodiimide (DCC). The reactionis allowed to stir for 2 h and is filtered under nitrogen. The anhydridesolution is then added to a solution of 1.0 g (2.4 mmol) of thehydrazide from step 1 in 75 mL of methylene chloride under nitrogen. Thereaction is stirred overnight, is concentrated to a volume of 25 mL, iscooled to 0° C., and is treated with 25 mL of TFA under nitrogen. Thestirred reaction is allowed to warm to ambient temperature overnight andis concentrated in vacuo. The crude product is dissolved in 100 mL ofacetonitrile/water (1:1) and the pH is adjusted to 8 with 1M K₂ CO₃. Thesolution is cooled to 0° C. and 0.23 mL (2.4 mmol) of acetic anhydrideand 2.4 mL (2.4 mmol) of 1M K₂ CO₃ is added every 30 min for 5 h; the pHis maintained at 9 and the reaction temperature is kept below 5° C.After the last addition, the reaction is allowed to warm to ambienttemperature overnight. The pH is adjusted to 4 with 3M HCl and thereaction is concentrated to 100 mL. Purification by reverse phasechromatography (Waters Deltaprep-3000) gives the product.

                                      TABLE V                                     __________________________________________________________________________     ##STR88##                                                                    Ex. #                                                                             R.sup.2                                                                             R.sup.1                                                                             L         B E  P                                              __________________________________________________________________________     83 CH.sub.2 OH                                                                         Cl    NH        H H  H                                               84 CH.sub.2 OH                                                                         Cl    NH        H CH.sub.3                                                                         H                                               85 CH.sub.2 OH                                                                         Cl    NH        H CH.sub.3                                                                         COCH.sub.3                                      86 CH.sub.2 OH                                                                         Cl    NH        H C.sub.2 H.sub.5                                                                  COCH.sub.3                                      87 CH.sub.2 OH                                                                         Cl    NH        H C.sub.2 H.sub.5                                                                  H                                               88 CH.sub.2 OH                                                                         Cl    NH        H H  COCH.sub.2 Cl                                   89 CH.sub.2 OH                                                                         Cl    NH        H H  COC.sub.4 H.sub. 9 (n)                          90 Cl    CH.sub.2 OH                                                                         NH        H H  H                                               91 CH.sub.2 OH                                                                         Cl    NHCH.sub.2 CH.sub.2                                                                     H H  COCH.sub.3                                      92 CH.sub.2 OH                                                                         Cl    NHCH.sub.2 CH.sub.2                                                                     H H  H                                               93 CH.sub.2 OH                                                                         Cl    NHCH.sub.2 CH.sub.2                                                                     H CH.sub.3                                                                         H                                               94 CH.sub.2 OH                                                                         Cl    NHCH.sub.2 CH.sub.2                                                                     H CH.sub.3                                                                         COCH.sub.3                                      95 CH.sub.2 OH                                                                         Cl    NHCH.sub.2 CH.sub.2                                                                     H C.sub.2 H.sub.5                                                                  COCH.sub.3                                      96 CH.sub.2 OH                                                                         Cl    NHCH.sub.2 CH.sub.2                                                                     H C.sub.2 H.sub.5                                                                  H                                               97 CH.sub.2 OH                                                                         Cl    NHCH.sub.2 CH.sub.2                                                                     H H  COCH.sub.2 Cl                                   98 CH.sub.2 OH                                                                         Cl    NHCH.sub.2 CH.sub.2                                                                     H H  COC.sub.4 H.sub.9 (n)                           99 Cl    CH.sub.2 OH                                                                         NHCH.sub.2 CH.sub.2                                                                     H H  COCH.sub.3                                     100 Cl    CH.sub.2 OH                                                                         NHCH.sub.2 CH.sub.2                                                                     H H  H                                              101 CH.sub.2 OH                                                                         Cl                                                                                   ##STR89##                                                                              * H  COCH.sub.3                                     102 CH.sub.2 OH                                                                         Cl                                                                                   ##STR90##                                                                              * H  H                                              103 CH.sub.2 OH                                                                         Cl                                                                                   ##STR91##                                                                              * CH.sub.3                                                                         H                                              104 CH.sub.2 OH                                                                         Cl                                                                                   ##STR92##                                                                              * CH.sub.3                                                                         COCH.sub.3                                     105 CH.sub.2 OH                                                                         Cl                                                                                   ##STR93##                                                                              * C.sub.2 H.sub.5                                                                  COCH.sub.3                                     106 CH.sub.2 OH                                                                         Cl                                                                                   ##STR94##                                                                              * C.sub.2 H.sub.5                                                                  H                                              107 CH.sub.2 OH                                                                         Cl                                                                                   ##STR95##                                                                              * H  COC.sub.4 H.sub.9 (n))                         108 CH.sub.2 OH                                                                         Cl                                                                                   ##STR96##                                                                              * H  COC.sub.4 H.sub.9 (n))                         109 Cl    CH.sub.2 OH                                                                          ##STR97##                                                                              * H  COCH.sub.3                                     110 Cl    CH.sub.2 OH                                                                          ##STR98##                                                                              * H  H                                              111 CH.sub.2 OCH.sub.3                                                                  Cl    NH        H H  COCH.sub.3                                     112 CH.sub.2 OCH.sub.3                                                                  Cl    NH        H H  H                                              113 Cl    CH.sub.2 OCH.sub.3                                                                  NH        H H  COCH.sub.3                                     114 Cl    CH.sub.2 OCH.sub.3                                                                  NH        H H  H                                              115 CH.sub.2 OH                                                                         CF.sub.3                                                                            NH        H H  COCH.sub.3                                     116 CH.sub.2 OH                                                                         CF.sub.3                                                                            NH        H H  H                                              117 CH.sub.2 OH                                                                         C.sub.2 F.sub.5                                                                     NH        H H  COCH.sub.3                                     118 CH.sub.2 OH                                                                         C.sub.2 F.sub.5                                                                     NH        H H  H                                              119 CH.sub.2 OH                                                                         C.sub.3 H.sub.7                                                                     NH        H H  COCH.sub.3                                     120 CH.sub.2 OH                                                                         C.sub.3 F.sub.7                                                                     NH        H H  H                                              121 CHO   Cl    NH        H H  COCH.sub.3                                     122 CHO   Cl    NH        H H  H                                              123 Cl    CHO   NH        H H  COCH.sub.3                                     124 Cl    CHO   NH        H H  H                                              125 CO.sub.2 H                                                                          Cl    NH        H H  COCH.sub.3                                     126 CO.sub.2 H                                                                          Cl    NH        H H  COCH.sub.3                                     127 Cl    CO.sub.2 H                                                                          NH        H H  COCH.sub.3                                     128 Cl    CO.sub.2 H                                                                          NH        H H  H                                              129 CH.sub.2 OH                                                                         Br    NH        H H  COCH.sub.3                                     130 CH.sub.2 OH                                                                         Br    NH        H H  H                                              131 Cl    CHO   NHCH.sub.2 CH.sub.2                                                                     H H  COCH.sub.3                                     132 Cl    CHO   NHCH.sub.2 CH.sub.2                                                                     H H  H                                              133 CO.sub.2 H                                                                          Cl    NHCH.sub.2 CH.sub.2                                                                     H H  COCH.sub.3                                     134 CO.sub.2 H                                                                          Cl    NHCH.sub.2 CH.sub.2                                                                     H H  H                                              135 Cl    CO.sub.2 H                                                                          NHCH.sub.2 CH.sub.2                                                                     H H  COCH.sub.3                                     136 Cl    CO.sub.2 H                                                                          NHCH.sub.2 CH.sub.2                                                                     H H  H                                              137 CH.sub.2 OH                                                                         Br    NHCH.sub.2 CH.sub.2                                                                     H H  COCH.sub.3                                     138 CH.sub.2 OH                                                                         Br    NHCH.sub.2 CH.sub.2                                                                     H H  H                                              139 Cl    CHO                                                                                  ##STR99##                                                                              * H  COCH.sub.3                                     140 Cl    CHO                                                                                  ##STR100##                                                                             * H  H                                              141 CO.sub.2 H                                                                          Cl                                                                                   ##STR101##                                                                             * H  COCH.sub.3                                     142 CO.sub.2 H                                                                          Cl                                                                                   ##STR102##                                                                             * H  H                                              143 Cl    CO.sub.2 H                                                                           ##STR103##                                                                             * H  COCH.sub.3                                     144 Cl    CO.sub.2 H                                                                           ##STR104##                                                                             * H  H                                              145 CH.sub.2 OH                                                                         Br                                                                                   ##STR105##                                                                             * H  COCH.sub.3                                     146 CH.sub.2 OH                                                                         Br                                                                                   ##STR106##                                                                             * H  H                                              __________________________________________________________________________     ##STR107##                                                               

Another class of highly preferred specific conjugates of the inventionis provided by conjugates formed from a biphenylmethyl 1H-substitutedimidazole AII antagonist compound having a terminal amino group attachedto the imidazole nucleus. In this family of conjugates, the cleavableglutamyl residue is attached through an amide bond formed between thecarbonyl at the gamma carbon of the glutamyl residue and the terminalamino nitrogen of the AII antagonist imidazole nucleus. Such conjugatesare shown as Examples #147-#710. General procedures for preparation ofthe conjugates of Examples #147-#710 are described in Schemes IV-V.Detailed procedures for preparation of representative conjugates aredescribed in Examples #147 and #148. Procedures similar to theseaforementioned general and specific procedures may be used forpreparation of the conjugates identified as Examples #149-#710 shown inTable VI.

EXAMPLE 147 ##STR108##N2-acetyl-N-[[2-butyl-4-chloro-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazol-5-yl]methyl]-L-glutamine

Step 1: Preparation of5-aminomethyl-2-butyl-4-chloro-1-[(2'-[1H-tetrazol-5-yl)biphenyl-4-methyl]imidazole.

A solution of 4.20 g (10 mmol) of the compound of Example 80, 7.7 g (100mmol) of ammonium acetate, and 439 mg (7 mmol) of NaBH₃ CN in 30 mL ofabsolute methanol is stirred at ambient temperature for 48 h.Concentrated HCl is added until pH<2, and the methanol is removed invacuo. The residue is dissolved in water and is extracted with ethylacetate. The aqueous solution is brought to pH>10 with 50% NaOH, issaturated with NaCl, and is extracted with methylene chloride. Theextracts are combined, are dried (MgSO₄), and are evaporated in vacuo togive the crude product. Purification by reverse phase chromatography(Waters DeltaPrep-3000) provides the pure 5-aminomethyl product.

Step 2: Preparation ofN2-acetyl-N-[[2-butyl-4-chloro-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazol-5-yl]methyl]-L-glutamine

To a solution of 1.70 g (5.6 mmol) of N-Boc-L-glutamic acid-o-tertbutylester (BACHEM) in 50 mL of methylene chloride under nitrogen is added580 mg (2.8 mmol) of solid dicylcohexylcarbodiimide (DCC). The reactionis allowed to stir for 2 h and is filtered under nitrogen. The anhydridesolution is then added to a solution of 1.01 g (2.4 mmol) of the5-aminomethyl compound of step 1 in 75 mL of methylene chloride undernitrogen. The reaction is stirred overnight, is concentrated to a volumeof 25 mL, is cooled to 0° C., and is treated with 25 mL of TFA undernitrogen. The stirred reaction is allowed to warm to ambient temperatureovernight and is concentrated in vacuo. The crude product is dissolvedin 100 mL of acetonitrile/water (1:1) and the pH is adjusted to 8 with1M K₂ CO₃. The solution is cooled to 0° C. and 0.23 mL (2.4 mmol) ofacetic anhydride and 2.4 mL (2.4 mmol) of 1M K₂ CO₃ is added every 30min for 5 h; the pH is maintained at 9 and the reaction temperature iskept below 5° C. After the last addition, the reaction is allowed towarm to ambient temperature overnight. The pH is adjusted to 4 with 3MHCl and the reaction is concentrated to 100 mL. Purification by reversephase chromatography (Waters Delta- prep-3000) gives the pure product.

EXAMPLE 148 ##STR109##N2-acetyl-N-[[2-butyl-5-chloro-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazol-4-yl]methyl]-L-glutamineStep 1: Preparation of2-butyl-5-chloro-4-formyl-1-(2'-(1H-tetrazol-5-yl)biphenyl-4-methyl]imidazole.

A mixture of 2.11 g (5.0 mmol) of the compound of Example 79 and 3.08 g(35 mmol) of activated manganese dioxide in 30 mL of methylene chlorideat ambient temperature is stirred for 40 h. The reaction mixture isfiltered through celite, and the filtrate is concentrated in vacuo.Purification by reverse phase chromatography provided the pure 4-formylproduct.

Step 2: Preparation of4-aminomethyl-2-butyl-5-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-methyl]imidazole.

A solution of 4.20 g (10 mmol) of the aldehyde from step 1, 7.7 g (100mmol) of ammonium acetate, and 439 mg (7 mmol) of NaBH₃ CN in 30 mL ofabsolute methanol is stirred at ambient temperature for 48 h.Concentrated HCl is added until pH<2, and the methanol is removed invacuo. The residue is dissolved in water and is extracted with ethylacetate. The aqueous solution is brought to pH>10 with 50% NaOH, issaturated with NaCl, and is extracted with methylene chloride. Theextracts are combined, are dried (MgSO₄), and are evaporated in vacuo togive the crude product. Purification by reverse phase chromatography(Waters Deltaprep-3000)) provides the pure product.

Step 3: Preparation ofN2-acetyl-N-[[2-butyl-5-chloro-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazol-4-yl]methyl]-L-glutamine

To a solution of 1.70 g (5.6 mmol) of N-Boc-L-glutamic acid-α-tertbutylester (BACHEM) in 50 mL of methylene chloride under nitrogen is added580 mg (2.8 mmol) of solid dicylcohexylcarbodiimide (DCC). The reactionis allowed to stir for 2 h and is filtered under nitrogen. The anhydridesolution is then added to a solution of 1.01 g (2.4 mmol) of the4-aminomethyl compound of step 2 in 75 mL of methylene chloride undernitrogen. The reaction is stirred overnight, is concentrated to a volumeof 25 mL, is cooled to 0° C., and is treated with 25 mL of TFA undernitrogen. The stirred reaction is allowed to warm to ambient temperatureovernight and is concentrated in vacuo. The crude product is dissolvedin 100 mL of acetonitrile/water (1:1) and the pH is adjusted to 8 with1M K₂ CO₃. The solution is cooled to 0° C. and 0.23 mL (2.4 mmol) ofacetic anhydride and 2.4 mL (2.4 mmol) of 1M K₂ CO₃ is added every 30min for 5 h; the pH is maintained at 9 and the reaction temperature iskept below 5° C. After the last addition, the reaction is allowed towarm to ambient temperature overnight. The pH is adjusted to 4 with 3MHCl and the reaction is concentrated to 100 mL. Purification by reversephase chromatography (Waters Delta-prep-3000) gives the pure product.

                                      TABLE VI                                    __________________________________________________________________________     ##STR110##                                                                   Ex: #                                                                             R.sup.1                                                                         R.sup.2                                                                         R.sub.5                                                                            A               B  E    P                                        __________________________________________________________________________    149 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  H    COCH.sub.3                               150 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  H    COCH.sub.2 Cl                            151 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  H    COC.sub.4 H.sub.9                        152 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  CH.sub.3                                                                           COCH.sub.3                               153 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    COCH.sub.3                               154 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  H    COCH.sub.3                               155 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  H    COCH.sub.2 Cl                            156 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  H    COC.sub.4 H.sub.9                        157 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  CH.sub.3                                                                           COCH.sub.3                               158 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    COCH.sub.3                               159 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  H    H                                        160 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  CH.sub.3                                                                           H                                        161 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    H                                        162 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  H    H                                        163 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  CH.sub.3                                                                           H                                        164 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    H                                        165 Cl                                                                              X CO.sub.2 H                                                                         CH.sub.2        H  H    COCH.sub.3                               166 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  H    COCH.sub.2 Cl                            167 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  H    COC.sub.4 H.sub.9                        168 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  CH.sub.3                                                                           COCH.sub.3                               169 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    COCH.sub.3                               170 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  H    COCH.sub.2 Cl                            171 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  H    COC.sub.4 H.sub.9                        172 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  CH.sub.3                                                                           COCH.sub.3                               173 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    COCH.sub.3                               174 Cl                                                                              X CO.sub.2 H                                                                         CH.sub.2        H  H    H                                        175 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  CH.sub.3                                                                           H                                        176 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    H                                        177 Cl                                                                              X CN.sub.4 H                                                                         CH.sub.2        H  H    H                                        178 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  CH.sub.3                                                                           H                                        179 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    H                                        180 Cl                                                                              X CN.sub.4 H                                                                         CH.sub.2        CH.sub.3                                                                         H    H                                        181 Cl                                                                              X CN.sub.4 H                                                                         CH.sub.2        CH.sub.3                                                                         H    COCH.sub.3                               182 Cl                                                                              X CO.sub.2 H                                                                         CH.sub.2 CH.sub.2                                                                             H  H    COCH.sub.3                               183 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  H    COCH.sub.2 Cl                            184 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  H    COC.sub.4 H.sub.9                        185 Cl                                                                              X CO.sub. 2 H                                                                        single bond     H  CH.sub.3                                                                           COCH.sub.3                               186 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    COCH.sub.3                               187 Cl                                                                              X CN.sub.4 H                                                                         CH.sub.2 CH.sub.2                                                                             H  H    COCH.sub.3                               188 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  H    COCH.sub.2 Cl                            189 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  H    COC.sub.4 H.sub.9                        190 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  CH.sub.3                                                                           COCH.sub.3                               191 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    COCH.sub.3                               192 Cl                                                                              X CO.sub.2 H                                                                         CH.sub.2 CH.sub.2                                                                             H  H    H                                        193 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  CH.sub.3                                                                           H                                        194 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    H                                        195 Cl                                                                              X CN.sub.4 H                                                                         CH.sub.2 CH.sub.2                                                                             H  H    H                                        196 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  CH.sub.3                                                                           H                                        197 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    H                                        198 Cl                                                                              X CO.sub.2 H                                                                         C.sub.3 H.sub.6 (n)                                                                           H  H    COCH.sub.3                               199 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  H    COCH.sub.2 Cl                            200 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  H    COC.sub.4 H.sub.9                        201 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  CH.sub.3                                                                           COCH.sub.3                               202 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    COCH.sub.3                               203 Cl                                                                              X CN.sub.4 H                                                                         C.sub.3 H.sub.6 (n)                                                                           H  H    COCH.sub.3                               204 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  H    COCH.sub.2 Cl                            205 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  H    COC.sub.4 H.sub.9                        206 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  CH.sub.3                                                                           COCH.sub.3                               207 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    COCH.sub.3                               208 Cl                                                                              X CO.sub.2 H                                                                         C.sub.3 H.sub.6 (n)                                                                           H  H    H                                        209 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  CH.sub.3                                                                           H                                        210 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    H                                        211 Cl                                                                              X CN.sub.4 H                                                                         C.sub.3 H.sub.6 (n)                                                                           H  H    H                                        212 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  CH.sub.3                                                                           H                                        213 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    H                                        214 Cl                                                                              X CO.sub.2 H                                                                         C.sub.4 H.sub.8 (n)                                                                           H  H    COCH.sub.3                               215 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  H    COCH.sub.2 Cl                            216 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  H    COC.sub.4 H.sub.9                        217 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  CH.sub.3                                                                           COCH.sub.3                               218 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    COCH.sub.3                               219 Cl                                                                              X CN.sub.4 H                                                                         C.sub.4 H.sub.8 (n)                                                                           H  H    COCH.sub.3                               220 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  H    COCH.sub.2 Cl                            221 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  H    COC.sub.4 H.sub.9                        222 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  CH.sub.3                                                                           COCH.sub.3                               223 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    COCH.sub.3                               224 Cl                                                                              X CO.sub.2 H                                                                         C.sub.4 H.sub.8 (n)                                                                           H  H    H                                        225 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  CH.sub.3                                                                           H                                        226 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    H                                        227 Cl                                                                              X CN.sub.4 H                                                                         C.sub.4 H.sub.8 (n)                                                                           H  H    H                                        228 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  CH.sub.3                                                                           H                                        229 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    H                                        230 Cl                                                                              X CO.sub.2 H                                                                          ##STR111##     H  H    COCH.sub.3                               231 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  H    COCH.sub.2 Cl                            232 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  H    COC.sub.4 H.sub.9                        233 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  CH.sub.3                                                                           COCH.sub.3                               234 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    COCH.sub.3                               235 Cl                                                                              X CN.sub.4 H                                                                          ##STR112##     H  H    COCH.sub.3                               236 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  H    COCH.sub.2 Cl                            237 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  H    COC.sub.4 H.sub.9                        238 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  CH.sub.3                                                                           COCH.sub.3                               239 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    COCH.sub.3                               240 Cl                                                                              X CO.sub.2 H                                                                          ##STR113##     H  H    H                                        241 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  CH.sub.3                                                                           H                                        242 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    H                                        243 Cl                                                                              X CN.sub.4 H                                                                          ##STR114##     H  H    H                                        244 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  CH.sub.3                                                                           H                                        245 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    H                                        246 Cl                                                                              X CO.sub.2 H                                                                          ##STR115##     H  H    COCH.sub.3                               247 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  H    COCH.sub.2 Cl                            248 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  H    COC.sub.4 H.sub.9                        249 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  CH.sub.3                                                                           COCH.sub.3                               250 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    COCH.sub.3                               251 Cl                                                                              X CN.sub.4 H                                                                          ##STR116##     H  H    COCH.sub.3                               252 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  H    COCH.sub.2 Cl                            253 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  H    COC.sub.4 H.sub.9                        254 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  CH.sub.3                                                                           COCH.sub.3                               255 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    COCH.sub.3                               256 Cl                                                                              X CO.sub.2 H                                                                          ##STR117##     H  H    H                                        257 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  CH.sub.3                                                                           H                                        258 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    H                                        259 Cl                                                                              X CN.sub.4 H                                                                          ##STR118##     H  H    H                                        260 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  CH.sub.3                                                                           H                                        261 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    H                                        262 Cl                                                                              X CO.sub.2 H                                                                          ##STR119##     H  H    COCH.sub.3                               263 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  H    COCH.sub.2 Cl                            264 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  H    COC.sub.4 H.sub.9                        265 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  CH.sub.3                                                                           COCH.sub.3                               266 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    COCH.sub.3                               267 Cl                                                                              X CN.sub.4 H                                                                          ##STR120##     H  H    COCH.sub. 3                              268 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  H    COCH.sub.2 Cl                            269 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  H    COC.sub.4 H.sub.9                        270 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  CH.sub.3                                                                           COCH.sub.3                               271 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    COCH.sub.3                               272 Cl                                                                              X CO.sub.2 H                                                                          ##STR121##     H  H    H                                        273 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  CH.sub.3                                                                           H                                        274 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    H                                        275 Cl                                                                              X CN.sub.4 H                                                                          ##STR122##     H  H    H                                        276 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  CH.sub.3                                                                           H                                        277 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    H                                        278 Cl                                                                              X CO.sub.2 H                                                                          ##STR123##     H  H    COCH.sub.3                               279 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  H    COCH.sub.2 Cl                            280 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  H    COC.sub.4 H.sub.9                        281 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  CH.sub.3                                                                           COCH.sub.3                               282 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    COCH.sub.3                               283 Cl                                                                              X CN.sub.4 H                                                                          ##STR124##     H  H    COCH.sub.3                               284 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  H    COCH.sub.2 Cl                            285 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  H    COC.sub.4 H.sub.9                        286 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  CH.sub.3                                                                           COCH.sub.3                               287 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    COCH.sub.3                               288 Cl                                                                              X CO.sub.2 H                                                                          ##STR125##     H  H    H                                        289 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  CH.sub.3                                                                           H                                        290 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    H                                        291 Cl                                                                              X CN.sub.4 H                                                                          ##STR126##     H  H    H                                        292 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  CH.sub.3                                                                           H                                        293 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    H                                        294 Cl                                                                              X CN.sub.4 H                                                                          ##STR127##     H  H    COCH.sub.3                               295 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  H    COCH.sub.2 Cl                            296 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  H    COC.sub.4 H.sub.9                        297 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  CH.sub.3                                                                           COCH.sub.3                               298 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    COCH.sub.3                               299 Cl                                                                              X CN.sub.4 H                                                                          ##STR128##     H  H    H                                        300 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  H    COCH.sub.2 Cl                            301 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  COC.sub.4 H.sub.9                             302 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  CH.sub.3                                                                           COCH.sub.3                               303 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    COCH.sub.3                               304 Cl                                                                              X CN.sub.4 H                                                                          ##STR129##     H  H    COCH.sub.3                               305 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  CH.sub.3                                                                           H                                        306 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    H                                        307 Cl                                                                              X CN.sub.4 H                                                                          ##STR130##     H  H    H                                        308 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  CH.sub.3                                                                           H                                        309 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    H                                        310 Cl                                                                              X CO.sub.2 H                                                                          ##STR131##     H  H    COCH.sub.3                               311 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  H    COCH.sub.2 Cl                            312 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  H    COC.sub.4 H.sub.9                        313 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  CH.sub.3                                                                           COCH.sub.3                               314 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    COCH.sub.3                               315 Cl                                                                              X CN.sub.4 H                                                                          ##STR132##     H  H    COCH.sub.3                               316 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  H    COCH.sub.2 Cl                            317 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  H    COC.sub.4 H.sub.9                        318 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  CH.sub.3                                                                           COCH.sub.3                               319 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    COCH.sub.3                               320 Cl                                                                              X CO.sub.2 H                                                                          ##STR133##     H  H    H                                        321 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  CH.sub.3                                                                           H                                        322 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    H                                        323 Cl                                                                              X CN.sub.4 H                                                                          ##STR134##     H  H    H                                        324 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  CH.sub.3                                                                           H                                        325 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    H                                        326 Cl                                                                              X CO.sub.2 H                                                                          ##STR135##     H  H    COCH.sub.3                               327 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  H    COCH.sub.2 Cl                            328 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  H    COC.sub.4 H.sub.9                        329 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  CH.sub.3                                                                           COCH.sub.3                               330 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    COCH.sub.3                               331 Cl                                                                              X CN.sub.4 H                                                                          ##STR136##     H  H    COCH.sub.3                               332 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  H    COCH.sub.2 Cl                            333 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  H    COC.sub.4 H.sub.9                        334 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  CH.sub.3                                                                           COCH.sub.3                               335 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    COCH.sub.3                               336 Cl                                                                              X CO.sub.2 H                                                                          ##STR137##     H  H    H                                        337 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  CH.sub.3                                                                           H                                        338 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    H                                        339 Cl                                                                              X CN.sub.4 H                                                                          ##STR138##     H  H    H                                        340 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  CH.sub.3                                                                           H                                        341 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    H                                        342 Cl                                                                              X CO.sub.2 H                                                                          ##STR139##     H  H    COCH.sub.3                               343 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  H    COCH.sub.2 Cl                            344 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  H    COC.sub.4 H.sub.9                        345 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  CH.sub.3                                                                           COCH.sub.3                               346 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    COCH.sub.3                               347 Cl                                                                              X CN.sub.4 H                                                                          ##STR140##     H  H    COCH.sub.3                               348 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  H    COCH.sub.2 Cl                            349 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  H    COC.sub.4 H.sub.9                        350 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  CH.sub.3                                                                           COCH.sub.3                               351 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    COCH.sub.3                               352 Cl                                                                              X CO.sub.2 H                                                                          ##STR141##     H  H    H                                        353 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  CH.sub.3                                                                           H                                        354 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    H                                        355 Cl                                                                              X CN.sub.4 H                                                                          ##STR142##     H  H    H                                        356 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  CH.sub.3                                                                           H                                        357 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    H                                        358 Cl                                                                              X CO.sub.2 H                                                                          ##STR143##     H  H    COCH.sub.3                               359 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  H    COCH.sub.2 Cl                            360 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  H    COC.sub.4 H.sub.9                        361 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  CH.sub.3                                                                           COCH.sub.3                               362 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    COCH.sub.3                               363 Cl                                                                              X CN.sub.4 H                                                                          ##STR144##     H  H    COCH.sub.3                               364 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  H    COCH.sub.2 Cl                            365 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  H    COC.sub.4 H.sub.9                        366 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  CH.sub.3                                                                           COCH.sub.3                               367 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    COCH.sub.3                               368 Cl                                                                              X CO.sub.2 H                                                                          ##STR145##     H  H    H                                        369 Cl                                                                              X CO.sub. 2 H                                                                        single bond     H  CH.sub.3                                                                           H                                        370 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    H                                        371 Cl                                                                              X CN.sub.4 H                                                                          ##STR146##     H  H    H                                        372 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  CH.sub.3                                                                           H                                        373 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    H                                        374 Cl                                                                              X CN.sub.4 H                                                                          ##STR147##     H  H    COCH.sub.3                               375 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  H    COCH.sub.2 Cl                            376 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  H    COC.sub.4 H.sub.9                        377 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  CH.sub.3                                                                           COCH.sub.3                               378 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    COCH.sub.3                               379 Cl                                                                              X CN.sub.4 H                                                                          ##STR148##     H  H    H                                        380 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  H    COCH.sub.2 Cl                            381 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  H    COC.sub.4 H.sub.9                        382 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  CH.sub.3                                                                           COCH.sub.3                               383 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    COCH.sub.3                               384 Cl                                                                              X CN.sub.4 H                                                                          ##STR149##     H  H    COCH.sub.3                               385 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  CH.sub.3                                                                           H                                        386 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    H                                        387 Cl                                                                              X CN.sub.4 H                                                                          ##STR150##     H  H    H                                        388 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  CH.sub.3                                                                           H                                        389 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    H                                        390 Cl                                                                              X CN.sub.4 H                                                                          ##STR151##     *  H    COCH.sub.3                               391 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  H    COCH.sub.2 Cl                            392 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  H    COC.sub.4 H.sub.9                        393 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  CH.sub.3                                                                           COCH.sub.3                               394 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    COCH.sub.3                               395 Cl                                                                              X CN.sub.4 H                                                                          ##STR152##     *  H    H                                        396 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  H    COCH.sub.2 Cl                            397 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  H    COC.sub.4 H.sub.9                        398 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  CH.sub.3                                                                           COCH.sub.3                               399 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    COCH.sub.3                               400 Cl                                                                              X CN.sub.4 H                                                                          ##STR153##     *  H    COCH.sub.3                               401 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  CH.sub.3                                                                           H                                        402 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    H                                        403 Cl                                                                              X CN.sub.4 H                                                                          ##STR154##     *  H    H                                        404 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  CH.sub.3                                                                           H                                        405 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    H                                        406 Cl                                                                              X CN.sub.4 H                                                                          ##STR155##     *  H    COCH.sub.3                               407 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  H    COCH.sub.2 Cl                            408 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  H    COC.sub.4 H.sub.9                        409 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  CH.sub.3                                                                           COCH.sub.3                               410 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    COCH.sub.3                               411 Cl                                                                              X CN.sub.4 H                                                                          ##STR156##     *  H    H                                        412 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  H    COCH.sub.2 Cl                            413 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  H    COC.sub.4 H.sub.9                        414 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  CH.sub.3                                                                           COCH.sub.3                               415 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    COCH.sub.3                               416 Cl                                                                              X CN.sub.4 H                                                                          ##STR157##     *  H    COCH.sub.3                               417 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  CH.sub.3                                                                           H                                        418 Cl                                                                              X CO.sub.2 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    H                                        419 Cl                                                                              X CN.sub.4 H                                                                          ##STR158##     *  H    H                                        420 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  CH.sub.3                                                                           H                                        421 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    H                                        422 Cl                                                                              X CN.sub.4 H                                                                          ##STR159##     *  H    COCH.sub.3                               423 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  H    COCH.sub.2 Cl                            424 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  H    COC.sub.4 H.sub.9                        425 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  CH.sub.3                                                                           COCH.sub.3                               426 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    COCH.sub.3                               427 Cl                                                                              X CN.sub.4 H                                                                          ##STR160##     *  H    H                                        428 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  CH.sub.3                                                                           H                                        429 Cl                                                                              X CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    H                                        430 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  H    COCH.sub.3                               431 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  H    COCH.sub.2 Cl                            432 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  H    COC.sub.4 H.sub.9                        433 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  CH.sub.3                                                                           COCH.sub.3                               434 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    COCH.sub.3                               435 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  H    COCH.sub.3                               436 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  H    COCH.sub.2 Cl                            437 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  H    COC.sub.4 H.sub.9                        438 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  CH.sub.3                                                                           COCH.sub.3                               439 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    COCH.sub.3                               440 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  H    H                                        441 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  CH.sub.3                                                                           H                                        442 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    H                                        443 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  H    H                                        444 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  CH.sub.3                                                                           H                                        445 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    H                                        446 X Cl                                                                              CO.sub.2 H                                                                         CH.sub.2        H  H    COCH.sub.3                               447 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  H    COCH.sub.2 Cl                            448 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  H    COC.sub.4 H.sub.9                        449 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  CH.sub.3                                                                           COCH.sub.3                               450 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    COCH.sub.3                               451 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  H    COCH.sub.2 Cl                            452 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  H    COC.sub.4 H.sub.9                        453 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  CH.sub.3                                                                           COCH.sub.3                               454 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    COCH.sub.3                               455 X Cl                                                                              CO.sub.2 H                                                                         CH.sub.2        H  H    H                                        456 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  CH.sub.3                                                                           H                                        457 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    H                                        458 X Cl                                                                              CN.sub.4 H                                                                         CH.sub.2        H  H    H                                        459 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  CH.sub.3                                                                           H                                        460 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    H                                        461 X Cl                                                                              CN.sub.4 H                                                                         CH.sub.2        CH.sub.3                                                                         H    H                                        462 X Cl                                                                              CN.sub.4 H                                                                         CH.sub.2        CH.sub.3                                                                         H    COCH.sub.3                               463 X Cl                                                                              CO.sub.2 H                                                                         CH.sub.2 CH.sub.2                                                                             H  H    COCH.sub.3                               464 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  H    COCH.sub.2 Cl                            465 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  H    COC.sub.4 H.sub.9                        466 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  CH.sub.3                                                                           COCH.sub.3                               467 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    COCH.sub.3                               468 X Cl                                                                              CN.sub.4 H                                                                         CH.sub.2 CH.sub.2                                                                             H  H    COCH.sub.3                               469 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  H    COCH.sub.2 Cl                            470 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  H    COC.sub.4 H.sub.9                        471 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  CH.sub.3                                                                           COCH.sub.3                               472 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    COCH.sub. 3                              473 X Cl                                                                              CO.sub.2 H                                                                         CH.sub.2 CH.sub.2                                                                             H  H    H                                        474 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  CH.sub.3                                                                           H                                        475 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    H                                        476 X Cl                                                                              CN.sub.4 H                                                                         CH.sub.2 CH.sub.2                                                                             H  H    H                                        477 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  CH.sub.3                                                                           H                                        478 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    H                                        479 X Cl                                                                              CO.sub.2 H                                                                         C.sub.3 H.sub.6 (n)                                                                           H  H    COCH.sub.3                               480 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  H    COCH.sub.2 Cl                            481 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  H    COC.sub.4 H.sub.9                        482 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  CH.sub.3                                                                           COCH.sub.3                               483 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    COCH.sub.3                               484 X Cl                                                                              CN.sub.4 H                                                                         C.sub.3 H.sub.6 (n)                                                                           H  H    COCH.sub.3                               485 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  H    COCH.sub.2 Cl                            486 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  H    COC.sub.4 H.sub.9                        487 X Cl                                                                              CN.sub. 4 H                                                                        single bond     H  CH.sub.3                                                                           COCH.sub.3                               488 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    COCH.sub.3                               489 X Cl                                                                              CO.sub.2 H                                                                         C.sub.3 H.sub.6 (n)                                                                           H  H    H                                        490 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  CH.sub.3                                                                           H                                        491 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    H                                        492 X Cl                                                                              CN.sub.4 H                                                                         C.sub.3 H.sub.6 (n)                                                                           H  H    H                                        493 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  CH.sub.3                                                                           H                                        494 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    H                                        495 X Cl                                                                              CO.sub.2 H                                                                         C.sub.4 H.sub.8 (n)                                                                           H  H    COCH.sub.3                               496 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  H    COCH.sub.2 Cl                            497 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  H    COC.sub.4 H.sub.9                        498 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  CH.sub.3                                                                           COCH.sub.3                               499 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    COCH.sub.3                               500 X Cl                                                                              CN.sub.4 H                                                                         C.sub.4 H.sub.8 (n)                                                                           H  H    COCH.sub.3                               501 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  H    COCH.sub.2 Cl                            502 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  H    COC.sub.4 H.sub.9                        503 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  CH.sub.3                                                                           COCH.sub.3                               504 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    COCH.sub.3                               505 X Cl                                                                              CO.sub.2 H                                                                         C.sub.4 H.sub.8 (n)                                                                           H  H    H                                        506 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  CH.sub.3                                                                           H                                        507 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    H                                        508 X Cl                                                                              CN.sub.4 H                                                                         C.sub.4 H.sub.8 (n)                                                                           H  H    H                                        509 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  CH.sub.3                                                                           H                                        510 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    H                                        511 X Cl                                                                              CO.sub.2 H                                                                          ##STR161##     H  H    COCH.sub.3                               512 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  H    COCH.sub.2 Cl                            513 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  H    COC.sub.4 H.sub.9                        514 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  CH.sub.3                                                                           COCH.sub.3                               515 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    COCH.sub.3                               516 X Cl                                                                              CN.sub.4 H                                                                          ##STR162##     H  H    COCH.sub.3                               517 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  H    COCH.sub.2 Cl                            518 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  H    COC.sub.4 H.sub.9                        519 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  CH.sub.3                                                                           COCH.sub.3                               520 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    COCH.sub.3                               521 X Cl                                                                              CO.sub.2 H                                                                          ##STR163##     H  H    H                                        522 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  CH.sub.3                                                                           H                                        523 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    H                                        524 X Cl                                                                              CN.sub.4 H                                                                          ##STR164##     H  H    H                                        525 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  CH.sub.3                                                                           H                                        526 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    H                                        527 X Cl                                                                              CO.sub.2 H                                                                          ##STR165##     H  H    COCH.sub.3                               528 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  H    COCH.sub.2 Cl                            529 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  H    COC.sub.4 H.sub.9                        530 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  CH.sub.3                                                                           COCH.sub.3                               531 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    COCH.sub.3                               532 X Cl                                                                              CN.sub.4 H                                                                          ##STR166##     H  H    COCH.sub.3                               533 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  H    COCH.sub.2 Cl                            534 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  H    COC.sub.4 H.sub.9                        535 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  CH.sub.3                                                                           COCH.sub.3                               536 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    COCH.sub.3                               537 X Cl                                                                              CO.sub.2 H                                                                          ##STR167##     H  H    H                                        538 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  CH.sub.3                                                                           H                                        539 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    H                                        540 X Cl                                                                              CN.sub.4 H                                                                          ##STR168##     H  H    H                                        541 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  CH.sub.3                                                                           H                                        542 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    H                                        543 X Cl                                                                              CO.sub.2 H                                                                          ##STR169##     H  H    COCH.sub.3                               544 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  H    COCH.sub.2 Cl                            545 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  H    COC.sub.4 H.sub.9                        546 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  CH.sub.3                                                                           COCH.sub.3                               547 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    COCH.sub.3                               548 X Cl                                                                              CN.sub.4 H                                                                          ##STR170##     H  H    COCH.sub.3                               549 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  H    COCH.sub.2 Cl                            550 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  H    COC.sub.4 H.sub.9                        551 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  CH.sub.3                                                                           COCH.sub.3                               552 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    COCH.sub.3                               553 X Cl                                                                              CO.sub.2 H                                                                          ##STR171##     H  H    H                                        554 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  CH.sub.3                                                                           H                                        555 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    H                                        556 X Cl                                                                              CN.sub.4 H                                                                          ##STR172##     H  H    H                                        557 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  CH.sub.3                                                                           H                                        558 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    H                                        559 X Cl                                                                              CO.sub.2 H                                                                          ##STR173##     H  H    COCH.sub.3                               560 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  H    COCH.sub.2 Cl                            561 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  H    COC.sub.4 H.sub.9                        562 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  CH.sub.3                                                                           COCH.sub.3                               563 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    COCH.sub.3                               564 X Cl                                                                              CN.sub.4 H                                                                          ##STR174##     H  H    COCH.sub.3                               565 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  H    COCH.sub.2 Cl                            566 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  H    COC.sub.4 H.sub.9                        567 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  CH.sub.3                                                                           COCH.sub.3                               568 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    COCH.sub.3                               569 X Cl                                                                              CO.sub.2 H                                                                          ##STR175##     H  H    H                                        570 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  CH.sub.3                                                                           H                                        571 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    H                                        572 X Cl                                                                              CN.sub.4 H                                                                          ##STR176##     H  H    H                                        573 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  CH.sub.3                                                                           H                                        574 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    H                                        575 X Cl                                                                              CN.sub.4 H                                                                          ##STR177##     H  H    COCH.sub.3                               576 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  H    COCH.sub.2 Cl                            577 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  H    COC.sub.4 H.sub.9                        578 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  CH.sub.3                                                                           COCH.sub.3                               579 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    COCH.sub.3                               580 X Cl                                                                              CN.sub.4 H                                                                          ##STR178##     H  H    H                                        581 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  H    COCH.sub.2 Cl                            582 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  H    COC.sub.4 H.sub.9                        583 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  CH.sub.3                                                                           COCH.sub.3                               584 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    COCH.sub.3                               585 X Cl                                                                              CN.sub.4 H                                                                          ##STR179##     H  H    COCH.sub.3                               586 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  CH.sub.3                                                                           H                                        587 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    H                                        588 X Cl                                                                              CN.sub.4 H                                                                          ##STR180##     H  H    H                                        589 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  CH.sub.3                                                                           H                                        590 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    H                                        591 X Cl                                                                              CO.sub.2 H                                                                          ##STR181##     H  H    COCH.sub.3                               592 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  H    COCH.sub.2 Cl                            593 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  H    COC.sub.4 H.sub.9                        594 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  CH.sub.3                                                                           COCH.sub.3                               595 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    COCH.sub.3                               596 X Cl                                                                              CN.sub.4 H                                                                          ##STR182##     H  H    COCH.sub.3                               597 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  H    COCH.sub.2 Cl                            598 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  H    COC.sub.4 H.sub.9                        599 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  CH.sub.3                                                                           COCH.sub.3                               600 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    COCH.sub.3                               601 X Cl                                                                              CO.sub.2 H                                                                          ##STR183##     H  H    H                                        602 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  CH.sub.3                                                                           H                                        603 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    H                                        604 X Cl                                                                              CN.sub.4 H                                                                          ##STR184##     H  H    H                                        605 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  CH.sub.3                                                                           H                                        606 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    H                                        607 X Cl                                                                              CO.sub.2 H                                                                          ##STR185##     H  H    COCH.sub.3                               608 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  H    COCH.sub.2 Cl                            609 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  H    COC.sub.4 H.sub.9                        610 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  CH.sub.3                                                                           COCH.sub.3                               611 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    COCH.sub.3                               612 X Cl                                                                              CN.sub.4 H                                                                          ##STR186##     H  H    COCH.sub.3                               613 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  H    COCH.sub.2 Cl                            614 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  H    COC.sub.4 H.sub.9                        615 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  CH.sub.3                                                                           COCH.sub.3                               616 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    COCH.sub.3                               617 X Cl                                                                              CO.sub.2 H                                                                          ##STR187##     H  H    H                                        618 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  CH.sub. 3                                                                          H                                        619 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    H                                        620 X Cl                                                                              CN.sub.4 H                                                                          ##STR188##     H  H    H                                        621 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  CH.sub.3                                                                           H                                        622 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    H                                        623 X Cl                                                                              CO.sub.2 H                                                                          ##STR189##     H  H    COCH.sub.3                               624 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  H    COCH.sub.2 Cl                            625 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  H    COC.sub.4 H.sub.9                        626 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  CH.sub.3                                                                           COCH.sub.3                               627 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    COCH.sub.3                               628 X Cl                                                                              CN.sub.4 H                                                                          ##STR190##     H  H    COCH.sub.3                               629 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  H    COCH.sub.2 Cl                            630 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  H    COC.sub.4 H.sub.9                        631 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  CH.sub.3                                                                           COCH.sub.3                               632 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    COCH.sub.3                               633 X Cl                                                                              CO.sub.2 H                                                                          ##STR191##     H  H    H                                        634 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  CH.sub.3                                                                           H                                        635 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    H                                        636 X Cl                                                                              CN.sub.4 H                                                                          ##STR192##     H  H    H                                        637 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  CH.sub.3                                                                           H                                        638 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    H                                        639 X Cl                                                                              CO.sub.2 H                                                                          ##STR193##     H  H    COCH.sub.3                               640 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  H    COCH.sub.2 Cl                            641 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  H    COC.sub.4 H.sub.9                        642 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  CH.sub.3                                                                           COCH.sub.3                               643 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    COCH.sub.3                               644 X Cl                                                                              CN.sub.4 H                                                                          ##STR194##     H  H    COCH.sub.3                               645 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  H    COCH.sub.2 Cl                            646 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  H    COC.sub.4 H.sub.9                        647 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  CH.sub.3                                                                           COCH.sub.3                               648 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    COCH.sub.3                               649 X Cl                                                                              CO.sub.2 H                                                                          ##STR195##     H  H    H                                        650 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  CH.sub.3                                                                           H                                        651 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    H                                        652 X Cl                                                                              CN.sub.4 H                                                                          ##STR196##     H  H    H                                        653 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  CH.sub.3                                                                           H                                        654 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    H                                        655 X Cl                                                                              CN.sub.4 H                                                                          ##STR197##     H  H    COCH.sub. 3                              656 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  H    COCH.sub.2 Cl                            657 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  H    COC.sub.4 H.sub.9                        658 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  CH.sub.3                                                                           COCH.sub.3                               659 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    COCH.sub.3                               660 X Cl                                                                              CN.sub.4 H                                                                          ##STR198##     H  H    H                                        661 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  H    COCH.sub.2 Cl                            662 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  H    COC.sub.4 H.sub.9                        663 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  CH.sub.3                                                                           COCH.sub.3                               664 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    COCH.sub.3                               665 X Cl                                                                              CN.sub.4 H                                                                          ##STR199##     H  H    COCH.sub.3                               666 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  CH.sub.3                                                                           H                                        667 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    H                                        668 X Cl                                                                              CN.sub.4 H                                                                          ##STR200##     H  H    H                                        669 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  CH.sub.3                                                                           H                                        670 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    H                                        671 X Cl                                                                              CN.sub.4 H                                                                          ##STR201##     *  H    COCH.sub.3                               672 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  H    COCH.sub.2 Cl                            673 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  H    COC.sub.4 H.sub.9                        674 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  CH.sub.3                                                                           COCH.sub.3                               675 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    COCH.sub.3                               676 X Cl                                                                              CN.sub.4 H                                                                          ##STR202##     *  H    H                                        677 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  H    COCH.sub.2 Cl                            678 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  H    COC.sub.4 H.sub.9                        679 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  CH.sub.3                                                                           COCH.sub.3                               680 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    COCH.sub.3                               681 X Cl                                                                              CN.sub.4 H                                                                          ##STR203##     *  H    COCH.sub.3                               682 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  CH.sub.3                                                                           H                                        683 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    H                                        684 X Cl                                                                              CN.sub.4 H                                                                          ##STR204##     *  H    H                                        685 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  CH.sub.3                                                                           H                                        686 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    H                                        687 X Cl                                                                              CN.sub.4 H                                                                          ##STR205##     *  H    COCH.sub.3                               688 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  H    COCH.sub.2 Cl                            689 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  H    COC.sub.4 H.sub.9                        690 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  CH.sub.3                                                                           COCH.sub.3                               691 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    COCH.sub.3                               692 X Cl                                                                              CN.sub.4 H                                                                          ##STR206##     *  H    H                                        693 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  H    COCH.sub.2 Cl                            694 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  H    COC.sub.4 H.sub.9                        695 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  CH.sub.3                                                                           COCH.sub.3                               696 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    COCH.sub.3                               697 X Cl                                                                              CN.sub.4 H                                                                          ##STR207##     *  H    COCH.sub.3                               698 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  CH.sub.3                                                                           H                                        699 X Cl                                                                              CO.sub.2 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    H                                        700 X Cl                                                                              CN.sub.4 H                                                                          ##STR208##     *  H    H                                        701 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  CH.sub.3                                                                           H                                        702 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    H                                        703 X Cl                                                                              CN.sub.4 H                                                                          ##STR209##     *  H    COCH.sub.3                               704 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  H    COCH.sub.2 Cl                            705 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  H    COC.sub.4 H.sub.9                        706 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  CH.sub.3                                                                           COCH.sub.3                               707 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    COCH.sub.3                               708 X Cl                                                                              CN.sub.4 H                                                                          ##STR210##     *  H    H                                        709 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  CH.sub.3                                                                           H                                        710 X Cl                                                                              CN.sub.4 H                                                                         single bond     H  C.sub.2 H.sub.5                                                                    H                                        __________________________________________________________________________     *B is incorporated in A                                                  

Another class of highly preferred specific conjugates of the inventionis provided by conjugates formed from a biphenylmethyl 1H-substitutedimidazole AII antagonist compound having a terminal carboxyl groupattached to the imidazo nucleus. In this family of conjugates, thecleavable glutamyl residue is attached through a diamino linker moietywhich connects the imidazo AII antagonist terminal carboxylic moietythrough two amide bonds to the gamma carbon of the glutamyl residue Suchconjugates are shown as Examples 711-1526. General procedures forpreparation of the conjugates of Examples #711-#1526 are described inSchemes VI-VII. Detailed procedures for preparation of representativeconjugates are described in Examples #711 and #712. Procedures similarto these aforementioned general and specific procedures may be used forpreparation of the conjugates identified as Examples #711-#1526 shown inTable VII.

EXAMPLE 711 ##STR211## N-acetyl-L-glutamic acid,5-[2-butyl-4-chloro-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazol-5-yl]acetylhydrazideStep 1: Preparation of2-butyl-5-cyanomethyl-4-chloro-1-(2'-(1H-tetrazol-5-yl)biphenyl-4-methyl]imidazole.

Thionyl chloride (7.2 mL, 98 mmol) is slowly dripped into a solution of8.45 g (20.0 mmol) of the compound of Example 78 in a minimum ofchloroform. The mixture is stirred for 2 h at ambient temperature andthe solvent is removed in vacuo. The chloride is dissolved indimethylsulfoxide (DMSO) and is added to a solution of 5.80 g (118 mmol)of sodium cyanide in 400 mL of DMSO. The solution is stirred overnightunder nitrogen at ambient temperature; water is added and the aqueouslayer is extracted with ethyl acetate. The extracts are combined, aredried (MgSO₄), and are concentrated in vacuo to give the crude product.Purification by silica gel chromatography (Waters DeltaPrep-500A)provides the pure 5-cyanomethyl derivative.

Step 2: Preparation of2-butyl-5-carboxymethyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-methyl]imidazole.

A solution of 6.5 g (15 mmol) of the 5-cyanomethyl derivative from step1 in 150 mL of concentrated hydrochloric acid/acetic acid (1:1) isstirred at reflux overnight. The solvents are removed in vacuo to givethe crude product. Purification by reverse phase chromatography (WatersDeltaprep-3000) provides the pure 5-acetic acid derivative.

Step 3: Preparation of2-butyl-4-chloro-5-methoxycarbonylmethyl-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-methyl]imidazole.

A solution of 4.5 g (10 mmol) of the 5-acetic acid derivative from step2 in 150 mL of absolute methanol is cooled to -10° C. and is treatedwith 1.5 mL (20 mmol) of thionyl chloride under nitrogen. The reactionis allowed to warm to ambient temperature and is stirred at refluxovernight. The methanol is removed in vacuo and the crude product isdissolved in water. The pH is adjusted to pH 4 with 1N NaOH and thesolution is extracted with ethyl acetate. The extracts are combined, aredried (MgSO₄), and are concentrated in vacuo to give the crude product.Purification by silica gel chromatography (Waters Prep-500A) providesthe pure 5-methyl acetate derivative.

Step 4: Preparation of 2-butyl-4-chloro-5-hydrazinylcarbonylmethyl-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-methyl]imidazole.

Under nitrogen, 2.32 g (5.0 mmol) of the 5-methyl acetate derivativefrom step 3 is dissolved in 50 mL of methanol and is treated with 5mL(160 mmol) of anhydrous hydrazine. The reaction is allowed to stir atreflux overnight; concentration in vacuo gives the crude material.Purification by silica gel chromatography (Waters Prep-500A) providesthe pure 5-acetic acid hydrazide derivative.

Step 5: Preparation of N-acetyl-L-glutamic acid,5-[2-butyl-4-chloro-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazol-5-yl]acetyl]hydrazide

To a solution of 1.70 g (5.6 mmol) glutamic acid-o-tertbutyl ester(BACHEM) in 50 mL of methylene chloride under nitrogen is added 580 mg(2.8 mmol) of solid dicylcohexylcarbodiimide (DCC). The reaction isallowed to stir for 2 h and is filtered under nitrogen. The anhydridesolution is then added to a solution of 1.01 g (2.4 mmol) of thehydrazide from step 4 in 75 mL of methylene chloride under nitrogen. Thereaction is stirred overnight, is concentrated to a volume of 25 mL, iscooled to 0° C., and is treated with 25 mL of TFA under nitrogen. Thestirred reaction is allowed to warm to ambient temperature overnight andis concentrated in vacuo. The crude product is dissolved in 100 mL ofacetonitrile/water (1:1) and the pH is adjusted to 8 with 1M K₂ CO₃. Thesolution is cooled to 0° C. and 0.23 mL (2.4 mmol) of acetic anhydrideand 2.4 mL (2.4 mmol) of 1M K₂ CO₃ is added every 30 min for 5 h; the pHis maintained at 9 and the reaction temperature is kept below 5° C.After the last addition, the reaction is allowed to warm to ambienttemperature overnight. The pH is adjusted to 4 with 3M HCl and thereaction is concentrated to 100 mL. Purification by reverse phasechromatography (Waters Deltaprep-3000) gives the pure product.

EXAMPLE 712 ##STR212## N-acetyl-L-glutamic acid,5-[2-butyl-5-chloro-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazol-4-yl]acetylhydrazideStep 1: Preparation of2-butyl-4-cyanomethyl-5-chloro-1-(2'-(1H-tetrazol-5-yl)biphenyl-4-methyl]imidazole.

Thionyl chloride (7.2 mL, 98 mmol) is slowly dripped into a solution of8.45 g (20.0 mmol) of the compound of Example 79 in a minimum ofchloroform. The mixture is stirred for 2 h at ambient temperature andthe solvent is removed in vacuo. The chloride is dissolved in DMSO andis added to a solution of 5.80 g (118 mmol) of sodium cyanide in 400 mLof DMSO. The solution is stirred overnight under nitrogen at ambienttemperature; water is added and the aqueous layer is extracted withethyl acetate. The extracts are combined, are dried (MgSO₄), and areconcentrated in vacuo to give the crude product. Purification by silicagel chromatography (Waters Prep-500A) provides the pure 4-cyanomethylderivative.

Step 2: Preparation of2-butyl-4-carboxymethyl-5-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-methyl]imidazole.

A solution of 6.5 g (15 mmol) of the 4-cyanomethyl derivative from step1 in 150 mL of concentrated hydrochloric acid/acetic acid (1:1) isstirred at reflux overnight. The solvents are removed in vacuo to givethe crude product. Purification by reverse phase chromatography provides(Waters Deltaprep-3000) the pure 4-acetic acid derivative.

Step 3: Preparation of2-butyl-5-chloro-4-methoxycarbonylmethyl-1-[(2'-(1H-tetrazol-5-yl]biphenyl-4-methyl]imidazole.

A solution of 4.5 g (10 mmol) of the 4-acetic acid derivative from step2 in 150 mL of absolute methanol is cooled to -10° C. and is treatedwith 1.5 mL (20 mmol) of thionyl chloride under nitrogen. The reactionis allowed to warm to ambient temperature and is stirred at refluxovernight. The methanol is removed in vacuo and the crude product isdissolved in water. The pH is adjusted to pH 4 with 1N NaOH and thesolution is extracted with ethyl acetate.

The extracts are combined, are dried (MgSO₄), and are concentrated invacuo to give the crude product. Purification by silica gelchromatography (Waters Prep-500A) provides the pure 4-methyl acetatederivative.

Step 4: Preparation of2-butyl-5-chloro-4-hydrazinylcarbonylmethyl-1-[(2'-(1H-tetrazole-5-yl)biphenyl-4-methyl]imidazole.

Under nitrogen, 2.32 g (5.0 mmol) of the 4-methyl acetate derivativefrom step 3 is dissolved in 50 mL of methanol and is treated with 5 mL(160 mmol) of anhydrous hydrazine. The reaction is allowed to stir atreflux overnight; concentration in vacuo gives the crude material.Purification by silica gel chromatography (Waters Prep-500A) providesthe pure 4-acetic acid hydrazide derivative.

Step 5: Preparation of N-acetyl-L-glutamic acid,5-[2-butyl-5-chloro-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazol-4-yl]acetylhydrazide

To a solution of 1.70 g (5.6 mmol) of N-Boc-L-glutamic acid-α-tertbutylester (BACHEM) in 50 mL of methylene chloride under nitrogen is added580 mg (2.8 mmol) of solid dicylcohexylcarbodiimide (DCC). The reactionis allowed to stir for 2 h and is filtered under nitrogen. The anhydridesolution is then added to a solution of 1.01 g (2.4 mmol) of thehydrazide from step 4 in 75 mL of methylene chloride under nitrogen. Thereaction is stirred overnight, is concentrated to a volume of 25 mL, iscooled to 0° C., and is treated with 25 mL of TFA under nitrogen. Thestirred reaction is allowed to warm to ambient temperature overnight andis concentrated in vacuo. The crude product is dissolved in 100 mL ofacetonitrile/water (1:1) and the pH is adjusted to 8 with 1M K₂ CO₃. Thesolution is cooled to 0° C. and 0.23 mL(2.4 mmol) of acetic anhydrideand 2.4 mL (2.4 mmol) of 1M K₂ CO₃ is added every 30 min for 5 h; the pHis maintained at 9 and the reaction temperature is kept below 5° C.After the last addition, the reaction is allowed to warm to ambienttemperature overnight. The pH is adjusted to 4 with 3M HCl and thereaction is concentrated to 100 mL. Purification by reverse phasechromatography (Waters Deltaprep-3000) gives the pure product.##STR213##

BIOLOGICAL EVALUATION

Compounds of Examples 1-80 are suitable angiotensin II antagonists foruse as the first component of conjugates of the invention. The AIIreceptor binding activity of many of the Example #1-#80 compounds, forexample, is described in EP #253,310 published Jan. 20, 1988. Thecompound of Example #5 was further evaluated in three biological assays(Assays "A", "B" and "C") for AII antagonist and blood pressure loweringproperties. In two other assays, blood-pressure lowering effects of theconjugate of Example #81 were evaluated (Assays "D" and "E").

Assay A: Angiotensin II Binding Activity

Compound of Example #5 was tested for ability to bind to the smoothmuscle angiotensin II receptor using a rat uterine membrane preparation.Angiotensin II (AII) was purchased from Peninsula Labs. 125I-angiotensinII (specific activity of 2200 Ci/mmol) was purchased from Du Pont-NewEngland Nuclear. Other chemicals were obtained from Sigma Chemical Co.This assay was carried out according to the method of Douglas et al[Endocrinology, 106, 120-124 (1980)]. Rat uterine membranes wereprepared from fresh tissue. All procedures were carried out at 4° C.Uteri were stripped of fat and homogenized in phosphate-buffered salineat pH 7.4 containing 5 mM EDTA. The homogenate was centrifuged at 1500×gfor 20 min., and the supernatant was recentrifuged at 100,000×g for 60min. The pellet was resuspended in buffer consisting of 2 mM EDTA and 50mM Tris-HCl (pH 7.5) to a final protein concentration of 4 mg/ml. Assaytubes were charged with 0.25 ml of a solution containing 5 mM MgCl₂, 2mM EDTA, 0.5% bovine serum albumin, 50 mM Tris-HCl, pH 7.5 and ¹²⁵ I-AII(approximately 10⁵ cpm) in the absence or in the presence of unlabelledligand. The reaction was initiated by the addition of membrane proteinand the mixture was incubated at 25° C. for 60 min. The incubation wasterminated with ice-cold 50 mM Tris-HCl (pH 7.5) and the mixture wasfiltered to separate membrane-bound labelled peptide from the freeligand. The incubation tube and filter were washed with ice-cold buffer.Filters were assayed for radioactivity in a Micromedic gamma counter.Nonspecific binding was defined as binding in the presence of 10 μM ofunlabelled AII. Specific binding was calculated as total binding minusnonspecific binding. The receptor binding affinity of an AII antagonistcompound was indicated by the concentration (IC₅₀) of the tested AIIantagonist which gives 50% displacement of the total specifically bound¹²⁵ I-AII from the high affinity AII receptor. Binding data wereanalyzed by a nonlinear least-squares curve fitting program. Results arereported in Table VIII.

Assay B: In Vitro Vascular Smooth Muscle-Response for AII

Compound of Example #5 was tested for AII antagonist activity in rabbitaortic rings. Male New Zealand white rabbits (2-2.5 kg) were sacrificedusing an overdose of pentobarbital and exsanguinated via the carotidarteries. The thoracic aorta was removed, cleaned of adherent fat andconnective tissue and then cut into 3-mm ring segments. The endotheliumwas removed from the rings by gently sliding a rolled-up piece of filterpaper into the vessel lumen. The rings were then mounted in awater-jacketed tissue bath, maintained at 37° C., between moveable andfixed ends of a stainless steel wire with the moveable end attached toan FT03 Grass transducer coupled to a Model 7D Grass Polygraph forrecording isometric force responses. The bath was filled with 20 ml ofoxygenated (95% oxygen/5% carbon dioxide) Krebs solution of thefollowing composition (nM): 130 NaCl, 15 NaHCO₃, 15 KCl, 1.2 NaH₂ PO₄,1.2 MgSO₄, 2.5 CaCl₂, and 11.4 glucose. The preparations wereequilibrated for one hour before approximately one gram of passivetension was placed on the rings. Angiotensin II concentration-responsecurves were then recorded (3×10⁻¹⁰ to 1×10⁻⁵ M). Each concentration ofAII was allowed to elicit its maximal contraction, and then AII waswashed out repeatedly for 30 minutes before rechallenging with a higherconcentration of AII. Aorta rings were exposed to the test antagonist at10⁻⁵ M for 5 minutes before challenging with AII. Adjacent segments ofthe same aorta ring were used for all concentration-response curves inthe presence or absence of the test antagonist. The effectiveness of thetest compound was expressed in terms of pA₂ values and were calculatedaccording to H. O. Schild [Br. J. Pharmacol. Chemother., 189-206(1947)]. The pA₂ value is the concentration of the test antagonistcompound which increases the EC₅₀ value for AII by a factor of two. Thetest compound was evaluated in aorta rings from three rabbits. Resultsare reported in Table VIII.

                  TABLE VIII                                                      ______________________________________                                        In Vitro Angiotensin II                                                       Activity of Compounds of Formula I                                                            .sup.1 Assay A                                                                IC.sub.50                                                                              .sup.2 Assay B                                       Test Compound   (nM)     PA.sub.2                                             ______________________________________                                        Ex. #5          216 ± 45                                                                            7.13 ± 0.16                                       ______________________________________                                         .sup.1 Assay A: In Vitro angiotensin II Binding Activity                      .sup.2 Assay B: Vascular Smooth Muscle Response                          

Assay C: In Vivo Intraduodenal and Intravenous Pressor Assay Responsefor AII Antagonists

The in vivo AII receptor antagonist activity of Example #5 compound wasexamined in ganglion-blocked male Sprague-Dawley rats (HarlanSprague-Dawley, Inc.), weighing 300-400 g, anesthetized with 100 mg/kgi.p. Inactin. Catheters (PE-50) were implanted in a femoral artery andvein to measure mean arterial pressure and to administer compounds,respectively. A tracheal catheter maintained airway patency. Forintravenous experiments, autonomic neurotransmission was blocked bytreatment with mecamylamine (3 mg/kg i.v.) and atropine (400 μg/kgi.v.). AII (30 ng/kg i.v., 20-25 μl volume) was administered four timesat 10 minute intervals to establish a reproducible control pressorresponse. Example #5 compound was then administered at 1, 3 and 10 mg/kgin separate groups of rats as an intravenous bolus (0.2 ml volume)before rechallenging with AII (30 ng/kg, 20-25 μl volume) for thefollowing 2 hours. For intraduodenal experiments, rats were anesthetizedas above, but ganglion blockade was not performed. AII was administeredat 100 ng/kg i.v. (20-25 μl volume), and was administered at 10, 30 and100 mg/kg in separate groups of rats as an intraduodenal bolus (0.2 mlvolume). Angiotensin II injections were then given 5, 10, 20, 30, 45,60, 75, 90, and 120 minutes after administration of the test compoundand response of arterial pressure was monitored. The response to AII wascalculated as percent of the control response and then the percentinhibition was calculated as 100 minus the percent control response.Duration of action of a test compound was defined as the time from peakpercent inhibition to 50% of peak. The test compound was tested in tworats and the values for the two rats were averaged. Results are reportedin Tables IX and X as percent of the control of AII pressor response,where "control" is defined as AII pressor response before the AIIantagonist test compound is administered.

                                      TABLE IX                                    __________________________________________________________________________    In Vivo Intravenous Angiotensin II                                            Activity of Example #5 Compound                                               (% Control of AII Pressor Response)                                           Dose Time (min)                                                               (mg/kg)                                                                            1  5  10 20 30 40 50 60 75 90 120                                        __________________________________________________________________________    1     80                                                                               85                                                                               92                                                                               90                                                                               88                                                                               86                                                                               86                                                                               89                                                                               93                                                                               95                                                                              100                                        n = 4                                                                              ±3                                                                            ±4                                                                            ±4                                                                            ±6                                                                            ±5                                                                            ±5                                                                            ±6                                                                            ±5                                                                            ±3                                                                            ±5                                                                            ±0                                      3     39                                                                               55                                                                               63                                                                               68                                                                               74                                                                               75                                                                               75                                                                               81                                                                               88                                                                               92                                                                               98                                        n = 4                                                                              ±5                                                                            ±7                                                                            ±8                                                                            ±6                                                                            ±7                                                                            ±5                                                                            ±3                                                                            ±7                                                                            ±7                                                                            ±5                                                                            ±1                                      10    4  16                                                                               23                                                                               31                                                                               40                                                                               47                                                                               51                                                                               60                                                                               71                                                                               80                                                                               96                                        n = 6                                                                              ±2                                                                            ±2                                                                            ±2                                                                            ±2                                                                            ± 3                                                                           ±4                                                                            ±4                                                                            ±6                                                                            ±7                                                                            ±8                                                                            ±6                                      __________________________________________________________________________

                  TABLE X                                                         ______________________________________                                        In Vivo Intraduodenal Angiotensin II Activity                                 of Example #5 Compound                                                        (% Control of AII Pressor Response)                                           Dose                                                                          (mg/  Time (min)                                                              kg)   1      5      10   20   30   40   50   60   75                          ______________________________________                                        10    100     94     99   85   91   91   95   93   95                         n = 3 ±0  ±4  ±1                                                                              ±11                                                                             +9   ±9                                                                              ±5                                                                              ±7                                                                              ±5                       30    48      48     44   28   34   42   41   53   74                         n = 4 ±4  ±7  ±11                                                                             ±5                                                                              ±4                                                                              ±6                                                                              ±0                                                                              ±2                                                                              ±7                       100   28      19     15   14   9    5    13   10   13                         n = 4 ±3  ±4  ±3                                                                              ±8                                                                              ±5                                                                              ±2                                                                              ±6                                                                              ±4                                                                              ±5                       ______________________________________                                    

Assay D: In Vivo Effects of Chronic Infusion of Conjugate of theInvention

A conjugate of the invention as synthesized in Example 81 was evaluatedbiologically by an in vivo assay to determine the ability of theconjugate to selectively inhibit renal action and thereby control bloodpressure. This in vivo experiment was conducted to characterize theeffects of the Example 81 conjugate on spontaneously hypertensive rats(SHR) by acute administration i.v. and by chronic administration i.v.The Example 81 compound or saline vehicle was infused continuously forfour days in SHR. Mean arterial pressure was measured (Gould ChartRecorder, model 3800; Statham P23Db pressure transducer) via anindwelling femoral artery catheter between 10:00 A. M. and 2:00 P. M.each day. The Example 81 conjugate (10 mg/hr) or saline was infused viaa jugular vein catheter with a Harvard infusion pump. Afteradministration of the Example 81 conjugate, there was observed a loweredmean arterial pressure as compared to the saline vehicle control asreported in Table XI and also in FIG. 1. A test was conducted todetermine whether the Example 81 conjugate would antagonize non-renal,vascular angiotensin II receptors. In this test AII was administered bybolus injection (100 ng/kg) to the SHR rats (described above) on thecontrol day and on days 1, 2 and 3 during conjugate infusion. Noevidence for systemic angiotensin II receptor antagonism was observed,given the similar pressor responses to injections of angiotensin II onthe control day and days 1, 2 and 3 of infusion of the Example 81conjugate as shown in Table XII and also in FIG. 2.

                  TABLE XI                                                        ______________________________________                                        Effect of Ex. #81 Conjugate on Mean                                           Arterial Pressure: Chronic Administration                                     ______________________________________                                        Time (days): Control   1          2    3                                      MAP (mm Hg)  163      148        135  140                                     ______________________________________                                    

                  TABLE XII                                                       ______________________________________                                        Effect of Ex. #81 Conjugate on                                                AII Pressor Response                                                          ______________________________________                                        Time (days):  Control   1         2   3                                       MAP (mm Hg)   44       45        65  60                                       ______________________________________                                    

Assay "E": In Vivo Effects of Acute Infusion of Conjugate of theInvention

In this assay, a comparison was made between an

antagonist compound (Ex. #5) and a glutamyl conjugate (Ex. #81) of theEx. #5 AII antagonist compound to determine the renal selectivity of theconjugate. Male Sprague-Dawley rats (300-350 g body weight) hadcatheters implanted into the femoral artery and vein under chloralhydrate anesthesia (400 mg/kg, i.p.). After 2 to 4 days of recovery, onthe experimental day, a urinary bladder catheter was implanted undermethohexital anesthesia (50 mg/kg, i.p.). Rats were placed in arestraint device to allow for urine collection and mean arterialpressure measurements. After 1-2 hours of recovery, in conscious rats,an isotonic saline infusion (50 μl/min) was started and continued forthe duration of the experiment. After one hour equilibration to thesaline infusion, a 20 minute control urine and mean arterial pressurecollection were obtained. Then angiotensin II was infused at 20 ng/minfor 25 minutes. After 5 minutes of angiotensin II infusion, a 20 minuteexperimental collection was made. Finally, 5 minutes after the end ofangiotensin II infusion, a 20 minute recovery collection was obtained.In separate groups of rats, vehicle (0.3 ml isotonic saline, i.v.bolus), Example #5 angiotensin II antagonist compound (100 mg/kg, i.v.bolus), or Example #81 conjugate (100 mg/kg, i.v. bolus) wasadministered 1-2 minutes prior to onset of angiotensin II infusion.Infusion of angiotensin II increased mean arterial pressure anddecreased urinary sodium excretion. The Example #5 AII antagonistcompound prevented both responses to angiotensin II. The Example #81conjugate had no effect on the mean arterial pressure response butprevented the antinatriuretic response to angiotensin II. Angiotensin IIinfusion following administration of Example #81 conjugate actuallyincreased urinary sodium excretion, probably due to a pressurenatriuresis. Results are shown in Tables XIII and XIV and also in FIGS.3 and 4. Data are presented as means±SE. Repeated measures analysis ofvariance was used for main effects and interactions and Tukey's HSD testwas used for pairwise comparisons among means. Statistical significancewas defined as p<0.05.

                  TABLE XIII                                                      ______________________________________                                        Effect of Ex. #81 Conjugate on                                                Urinary Sodium Excretion (μEq/min/100 g BW)                                       Control    AII       Recovery                                          ______________________________________                                        Vehicle  1.9 ± 0.8 0.8 ± 0.3*                                                                           1.7 ± 0.5                                  Ex. #5   2.4 ± 0.5 2.5 ± 1.1                                                                            2.6 ± 0.7                                  Ex. #81  1.3 ± 0.3 4.1 ± 1.3*                                                                           1.8 ± 0.4                                  ______________________________________                                    

                  TABLE XIV                                                       ______________________________________                                        Effect of Ex. #81 Conjugate on Mean                                           Arterial Pressure (mm Hg): Acute Administration                                          Control  AII      Recovery                                         ______________________________________                                        Vehicle (n = 6)                                                                            121 ± 3 155 ± 3*                                                                            123 ± 4                                   Ex. #5  (n = 6)                                                                            123 ± 5 125 ± 7                                                                             124 ± 7                                   Ex. #81 (n = 6)                                                                            117 ± 3 151 ± 4*                                                                            121 ± 4                                   ______________________________________                                    

Also embraced within this invention is a class of pharmaceuticalcompositions comprising one or more conjugates which comprises a firstcomponent selected from angiotensin II antagonist compounds of Formula Ilinked to a second component provided by an enzyme-cleavable moiety.Such pharmaceutical compositions further comprise one or more non-toxic,pharmaceutically acceptable carriers and/or diluents and/or adjuvants(collectively referred to herein as "carrier" materials) and, ifdesired, other active ingredients. The conjugates of the presentinvention may be administered by any suitable route, preferably in theform of a pharmaceutical composition adapted to such a route, and in adose effective for the treatment intended. Therapeutically effectivedoses of a conjugate of the present invention required to prevent orarrest the progress of the medical condition are readily ascertained byone of ordinary skill in the art. The conjugates and composition may,for example, be administered intravascularly, intraperitoneally,subcutaneously, intramuscularly or topically.

For oral administration, the pharmaceutical composition may be in theform of, for example, a tablet, capsule, suspension or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a particular amount of the conjugate. Examples of suchdosage units are tablets or capsules. These may with advantage containan amount of conjugate from about 1 to 250 mg, preferably from about 25to 150 mg. A suitable daily dose for a mammal may vary widely dependingon the condition of the patient and other factors. However, a dose offrom about 0.1 to 3000 mg/kg body weight, particularly from about 1 to100 mg/kg body weight, may be appropriate.

The conjugate may also be administered by injection as a compositionwherein, for example, saline, dextrose or water may be used as asuitable carrier. A suitable daily dose is from about 0.1 to 100 mg/kgbody weight injected per day in multiple doses depending on the diseasebeing treated. A preferred daily dose would be from about 1 to 30 mg/kgbody weight. Conjugates indicated for prophylactic therapy willpreferably be administered in a daily dose generally in a range fromabout 0.1 mg to about 100 mg per kilogram of body weight per day. A morepreferred dosage will be a range from about 1 mg to about 100 mg perkilogram of body weight. Most preferred is a dosage in a range fromabout 1 to about 50 mg per kilogram of body weight per day. A suitabledose can be administered, in multiple sub-doses per day. These sub-dosesmay be administered in unit dosage forms. Typically, a dose or sub-dosemay contain from about 1 mg to about 100 mg of active compound per unitdosage form. A more preferred dosage will contain from about 2 mg toabout 50 mg of active compound per unit dosage form. Most preferred is adosage form containing from about 3 mg to about 25 mg of active compoundper unit dose.

The dosage regimen for treating a disease condition with the conjugatesand/or compositions of this invention is selected in accordance with avariety of factors, including the type, age, weight, sex and medicalcondition of the patient, the severity of the disease, the route ofadministration, and the particular conjugate employed, and thus may varywidely.

For therapeutic purposes, the conjugates of this invention areordinarily combined with one or more adjuvants appropriate to theindicated route of administration. If administered per os, the conjugatemay be admixed with lactose, sucrose, starch powder, cellulose esters ofalkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesiumstearate, magnesium oxide, sodium and calcium salts of phosphoric andsulfuric acids, gelatin, acacia gum, sodium alginate,polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted orencapsulated for convenient administration. Such capsules or tablets maycontain a controlled-release formulation as may be provided in adispersion of conjugate in hydroxypropylmethyl cellulose. Formulationsfor parenteral administration may be in the form of aqueous ornon-aqueous isotonic sterile injection solutions or suspensions. Thesesolutions and suspensions may be prepared from sterile powders orgranules having one or more of the carriers or diluents mentioned foruse in the formulations for oral administration. The conjugates may bedissolved in water, polyethylene glycol, propylene glycol, ethanol, cornoil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodiumchloride, and/or various buffers. Other adjuvants and modes ofadministration are well and widely known in the pharmaceutical art.

Although this invention has been described with respect to specificembodiments, the details of these embodiments are not to be construed aslimitations. Various equivalents, changes and modifications may be madewithout departing from the spirit and scope of this invention, and it isunderstood that such equivalent embodiments are part of this invention.

What is claimed is:
 1. A renal selective conjugate consisting of a firstradical and a second radical, said first and second radicals connectedtogether by a kidney-enzyme-cleavable bond, wherein said first radicalis provided by a biphenylalkyl 1H-substituted-1,3-imidazole angiotensinII antagonist compound of Formula I: ##STR214## wherein m is one;wherein R⁰ is selected from C₄ H₉ (n), CH₃ CH₂ CH═CH, C₃ H₇ (N), SC₃ H₇,##STR215## C₂ H₅, C₅ H₁₁ (n), C₆ H₁₃ (n), SC₄ H₉, ##STR216## CH₃ CH═CHand CH₃ CH₂ CH₂ CH═CH--; wherein R¹ is selected from amino, aminomethyl,aminoethyl, aminopropyl, CH₂ OH, CH₂ OCOCH₃, CH₂ Cl, F, Cl, Br, I, CH₂OCH₃, CH₂ OCH(CH₃)₂, CHO, CH₂ CO₂ H, CH(CH₃)CO₂ H, --CO₂ CH₃, --CONH₂,--CONHCH₃, CON(CH₃)₂, --CH₂ --NHCO₂ C₂ H₅, ##STR217## --CH₂ NHCO₂ CH₃,--CH₂ NHCO₂ C₃ H₇, --CH₂ NHCO₂ CH₂ (CH₃) ₂, --CH₂ NHCO₂ C₄ H₉, CH₂ NHCO₂-adamantyl, --CH₂ NHCO₂ -(1-naphthyl), --CH₂ NHCONHCH₃, --CH₂ NHCONHC₂H₅, --CH₂ NHCONHC₃ H₇, --CH₂ NHCONHC₄ H₉, --CH₂ NHCONHCH(CH₃)₂, --CH₂NHCONH(1-naphthyl), --CH₂ NHCONH(1-adamantyl), --CH₂ CH₂ CH₂ CO₂ H,--CH₂ CH₂ F, --CH₂ OCONHCH₃, --CH₂ CH₂ CH₂ F, --CH₂ SH and ##STR218##wherein R² is selected from H, F, Cl, Br, I, NO₂, CF₃, CH₂ OH, methyl,ethyl, n-propyl, isoproyl, n-butyl, sec-butyl, isobutyl, tert-butyl,n-pentyl, isopentyl, neopentyl, phenyl, benzyl, phenethyl, cyclohexyl,cyclohexylmethyl, 1-oxoethyl, 1-oxopropyl, 1-oxobutyl, 1-oxopentyl,1,1-dimethoxypropyl, 1,1-dimethoxybutyl, 1,1-dimethoxypentyl,hydroxyalkyl, difluoromethyl, 1,1-difluoroethyl, 1,1-difluoropropyl,1,1-difluorobutyl and 1,1-difluoropentyl; with the proviso that at leastone of R⁵, R⁶, R⁸ and R⁹ is an acidic group selected from CO₂ H, SH, SO₃H and ##STR219## and wherein each of the remainder of R³ through R¹¹ ishydrido, with the further proviso that at least one of said R¹ throughR¹¹ is a substituent selected from COOH and moieties containing aterminal primary or secondary amino group; or a tautomer thereof or apharmaceutically-acceptable salt thereof;wherein said second radical isprovided by a compound selected from a class of compounds of Formula II:##STR220## wherein each of R⁵⁰ and R⁵¹ may be independently selectedfrom hydrido, alkylcarbonyl, alkoxycarbonyl, alkoxyalkyl, hydroxyalkyland haloalkyl; and wherein G is selected from hydrido, hydroxyl, halo,mercapto, --OR⁵², --SR⁵³ and ##STR221## with each of R⁵², R⁵³ and R⁵⁴independently selected from alkyl, and wherein each of R⁵³ and R⁵⁴ maybe further independently selected from hydrido; with the proviso thatsaid kidney-enzyme-cleavable bond is within an amide group formedbetween said first and second radicals, wherein said first radical has aterminal primary or secondary amino moiety, wherein said first-radicalamino moiety is provided by one of said R¹ through R¹¹ substituents ofsaid Formula I compound or is provided by a linking moiety attached to acarbonyl group attached at one of said R¹ through R¹¹ substituents ofsaid Formula I, and wherein said second radical has a carbonyl moietyattached at the gamma-position carbon of said Formula II compound,whereby said amide bond is formed from said first-radical amino moietyand said second radical carbonyl moiety; and wherein said linking moietyis a divalent radical of Formula III: ##STR222## wherein each of R²⁰⁰and R²⁰¹ may be independently selected from hydrido, alkyl, cycloaklyl,cycloalkylalkyl, alkoxyalkyl, hydroxyalkyl and haloalkyl; and wherein nis a number selected from zero through six, inclusive; or apharmaceutically-acceptable salt of said renal-selective conjugate. 2.Conjugate of claim 1 wherein m is one; wherein R⁰ is selected from C₄ H₉(n), CH₃ CH₂ CH═CH, C₃ H₇ (N), SC₃ H₇, ##STR223## C₂ H₅, C₅ H₁₁ (n), C₆H₁₃ (n), SC₄ H₉, ##STR224## CH₃ CH═CH and CH₃ CH₂ CH₂ CH═CH--; whereinR¹ is selected from H, NO₂, CF₃, CH₂ OH, F, Cl, Br, I, methyl, ethyl,n-propyl isoproyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl,isopentyl, neopentyl, phenyl, benzyl, phenethyl, cyclohexyl,cyclohexylmethyl, 1-oxoethyl, 1-oxopropyl, 1-oxobutyl, 1-oxopentyl,1,1-dimethoxypropyl, 1,1-dimethoxybutyl, 1,1-dimethoxypentyl,hydroxyalkyl, difluoromethyl, 1,1-difluoroethyl, 1,1-difluoropropyl,1,1-difluorobutyl and 1,1-difluoropentyl; wherein R² is selected fromamino, aminomethyl, aminoethyl, aminopropyl, CH₂ OH, CH₂ OCOCH₃, CH₂ Cl,CH₂ OCH₃, CH₂ OCH(CH₃)₂, F, Cl, Br, I, CHO, CH₂ CO₂ H, CH(CH₃)CO₂ H,--CO₂ CH₃, --CONH₂, --CONHCH₃, CON(CH₃)₂, --CH₂ NHCO₂ C₂ H₅, ##STR225##--CH₂ NHCO₂ CH₃, --CH₂ NHCO₂ C₃ H₇, --CH₂ NHCO₂ CH₂ (CH₃)₂, --CH₂ NHCO₂C₄ H₉, CH₂ NHCO₂ -adamantyl, --CH₂ NHCO₂ -(1-naphthyl), --CH₂ NHCONHCH₃,--CH₂ NHCONHC₂ H₅, --CH₂ NHCONHC₃ H₇ --CH₂ NHCONHC₄ H₉, --CH₂NHCONHCH(CH₃)₂, --CH₂ NHCONH(1-naphthyl), --CH₂ NHCONH(1-adamantyl), CO₂H, --CH₂ CH₂ CH₂ CO₂ H, --CH₂ CH₂ F, CH₂ OCONHCH₃, --CH₂ CH₂ CH₂ F,--CH₂ SH and ##STR226## with the proviso that at least one of R⁵, R⁶, R⁸and R⁹ is an acidic group selected from COOH and ##STR227## and whereineach of the remainder of R³ through R¹¹ is hydrido, with the furtherproviso that at least one of said R¹ through R¹¹ is a substituentselected from COOH and moieties containing a terminal primary orsecondary amino group; or a tautomer thereof or apharmaceutically-acceptable salt thereof.
 3. Conjugate of claim 1wherein each G substituent is hydroxy.
 4. Conjugate of claim 1 whereineach G substituent is hydroxy; wherein R⁵⁰ is hydrido; and wherein R⁵¹is selected from ##STR228## wherein R⁵⁵ is selected from methyl, ethyl,n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl,n-pentyl, neopentyl, n-hexyl and chloromethyl.
 5. Conjugate of claim 1wherein said second radical is ##STR229##
 6. Conjugate of claim 1wherein said first radical is a biphenylalkyl1H-substituted-1,3-imidazole angiotensin II antagonist compoundcontaining a terminal primary or secondary amino moiety attached at oneof said R¹ through R¹¹ positions of Formula I, said amino moietyselected from amino and linear or branched aminoalkyl moietiescontaining linear or branched alkyl groups selected from aminomethyl,aminoethyl, aminopropyl, aminoisopropyl, aminobutyl, aminosecbutyl,aminoisobutyl, aminotertbutyl, aminopentyl, aminoisopentyl andaminoneopentyl.
 7. Conjugate of claim 1 wherein each of R²⁰⁰ and R²⁰¹ ishydrido.
 8. Conjugate of claim 1 wherein said angiotensin II antagonistcompound is4'-[2-butyl-5-chloro-4-(hydroxymethyl)-1H-imidazol-1-ylmethyl][1,1'-biphenyl]-2-carboxylicacid or a pharmaceutically-acceptable salt thereof.
 9. Conjugate ofclaim 8 which is N-acetyl-L-glutamic acid,5-[[4'-[2-butyl-5-chloro-4-(hydroxymethyl)-1H-imidazol-1-ylmethyl][1,1'-biphenyl]-2-yl]carbonyl]hydrazideor a pharmaceutically-acceptable salt thereof.
 10. Conjugate of claim 8which is N²-acetyl-N-[[2-butyl-5-chloro-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazol-4-yl]methyl]-L-glutamineor a pharmaceutically-acceptable salt thereof.
 11. Conjugate of claim 8which is N-acetyl-N-L-glutamic acid,5-[2-butyl-5-chloro-1-[[2'-(1H-tetrazol-5-yl)[1,1-biphenyl]-4-yl]methyl]-1H-imidazol-4-yl]acetylhydrazideor a pharmaceutically-acceptable salt thereof.
 12. Conjugate of claim 1wherein said angiotensin II antagonist compound is4'-[2-butyl-4-chloro-5-(hydroxymethyl)-1H-imidazol-1-ylmethyl][1,1'-biphenyl]-2-carboxylicacid or a pharmaceutically-acceptable salt thereof.
 13. Conjugate ofclaim 12 which is N-acetyl-L-glutamic acid,5-[[4'-[2-butyl-4-chloro-5-(hydroxymethyl)-1H-imidazol-1-ylmethyl][1,1'-biphenyl]-2-yl]carbonyl]hydrazideor a pharmaceutically-acceptable salt thereof.
 14. Conjugate of claim 12which is N²-acetyl-N-[[2-butyl-4-chloro-1-[[2'-(1H-biphenyl-4-yl)methyl]-1H-imidazol-5-yl]methyl]-L-glutamineor a pharmaceutically-acceptable salt thereof.
 15. Conjugate of claim 12which is N-acetyl-L-glutamic acid,5-[2-butyl-4-chloro-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazol-5-yl]acetylhydrazideor a pharmaceutically-acceptable salt thereof.
 16. A pharmaceuticalcomposition comprising one or more pharmaceutically-acceptable carriersor diluents and a therapeutically-effective amount of a renal-selectiveconjugate, said renal selective conjugate consisting of a first radicaland a second radical, said first and second radicals connected togetherby a kidney-enzyme-cleavable bond, wherein said first radical isprovided by a biphenylalkyl 1H-substituted-1,3-imidazole angiotensin IIantagonist compound of Formula I: ##STR230## wherein m is one; whereinR⁰ is selected from C₄ H₉ (n), CH₃ CH₂ CH═CH, C₃ H₇ (N), SC₃ H₇,##STR231## C₂ H₅, C₅ H₁₁ (n), C₆ H₁₃ (n), SC₄ H₉, ##STR232## CH₃ CH═CHand CH₃ CH₂ CH₂ CH═CH--; wherein R¹ is selected from amino, aminomethyl,aminoethyl, aminopropyl, CH₂ OH, CH₂ OCOCH₃, CH₂ Cl, F, Cl, Br, I, CH₂OCH₃, CH₂ OCH(CH₃)₂, CHO, CH₂ CO₂ H, CH(CH₃)CO₂ H, --CO₂ CH₃, --CONH₂,--CONHCH₃, CON(CH₃)₂, --CH₂ --NHCO₂ C₂ H₅, ##STR233## --CH₂ NHCO₂ CH₃,--CH₂ NHCO₂ C₃ H₇, --CH₂ NHCO₂ CH₂ (CH₃) ₂, --CH₂ NHCO₂ C₄ H₉, CH₂ NHCO₂-adamantyl, --CH₂ NHCO₂ -(1-naphthyl), --CH₂ NHCONHCH₃, --CH₂ NHCONHC₂H₅, --CH₂ NHCONHC₃ H₇, --CH₂ NHCONHC₄ H₉, --CH₂ NHCONHCH(CH₃)₂, --CH₂NHCONH(1-naphthyl), --CH₂ NHCONH(1-adamantyl), --CH₂ CH₂ CH₂ CO₂ H,--CH₂ CH₂ F, --CH₂ OCONHCH₃, --CH₂ CH₂ CH₂ F, --CH₂ SH and ##STR234##wherein R² is selected from H, F, Cl, Br, I, NO₂, CF₃, CH₂ OH, methyl,ethyl, n-propyl, isoproyl, n-butyl, sec-butyl, isobutyl, tert-butyl,n-pentyl, isopentyl, neopentyl, phenyl, benzyl, phenethyl, cyclohexyl,cyclohexylmethyl, 1-oxoethyl, 1-oxopropyl, 1-oxobutyl, 1-oxopentyl,1,1-dimethoxypropyl, 1,1-dimethoxybutyl, 1,1-dimethoxypentyl,hydroxyalkyl, difluoromethyl, 1,1-difluoroethyl, 1,1-difluoropropyl,1,1-difluorobutyl and 1,1-difluoropentyl; with the proviso that at leastone of R⁵, R⁶, R⁸ and R⁹ is an acidic group selected from CO₂ H, SH, SO₃H and ##STR235## and wherein each of the remainder of R³ through R¹¹ ishydrido, with the further proviso that at least one of said R¹ throughR¹¹ is a substituent selected from COOH and moieties containing aterminal primary or secondary amino group; or a tautomer thereof or apharmaceutically-acceptable salt thereof;wherein said second radical isprovided by a compound selected from a class of compounds of Formula II:##STR236## wherein each of R⁵⁰ and R⁵¹ may be independently selectedfrom hydrido, alkylcarbonyl, alkoxycarbonyl, alkoxyalkyl, hydroxyalkyland haloalkyl; and wherein G is selected from hydrido, hydroxyl, halo,mercapto, --OR⁵², --SR⁵³ and ##STR237## with each of R⁵², R⁵³ and R⁵⁴independently selected from alkyl, and wherein each of R⁵³ and R⁵⁴ maybe further independently selected from hydrido; with the proviso thatsaid kidney-enzyme-cleavable bond is within an amide group formedbetween said first and second radicals, wherein said first radical has aterminal primary or secondary amino moiety, wherein said first-radicalamino moiety is provided by one of said R¹ through R¹¹ substituents ofsaid Formula I compound or is provided by a linking moiety attached to acarbonyl group attached at one of said R¹ through R¹¹ substituents ofsaid Formula I, and wherein said second radical has a carbonyl moietyattached at the gamma-position carbon of said Formula II compound,whereby said amide bond is formed from said first-radical amino moietyand said second radical carbonyl moiety; and wherein said linking moietyis a divalent radical of Formula III: ##STR238## wherein each of R²⁰⁰and R²⁰¹ may be independently selected from hydrido, alkyl, cycloaklyl,cycloalkylalkyl, alkoxyalkyl, hydroxyalkyl and haloalkyl; and wherein nis a number selected from zero through six, inclusive; or apharmaceutically-acceptable salt of said renal-selective conjugate. 17.The composition of claim 16 wherein m is one; wherein R⁰ is selectedfrom C₄ H₉ (n), CH₃ CH₂ CH═CH, C₃ H₇ (N), SC₃ H₇, ##STR239## C₂ H₅, C₅H₁₁ (n), C₆ H₁₃ (n), SC₄ H₉, ##STR240## CH₃ CH═CH and CH₃ CH₂ CH₂CH═CH--; wherein R¹ is selected from H, NO₂, CF₃, CH₂ OH, F, Cl, Br, I,methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl,tert-butyl, n-pentyl, isopentyl, neopentyl, phenyl, benzyl, phenethyl,cyclohexyl, cyclohexylmethyl, 1-oxoethyl, 1-oxopropyl, 1-oxobutyl,1-oxopentyl, 1,1-dimethoxypropyl, 1,1-dimethoxybutyl,1,1-dimethoxypentyl, hydroxyalkyl, difluoromethyl, 1,1-difluoroethyl,1,1-difluoropropyl, 1,1-difluorobutyl and 1,1-difluoropenyl; wherein R²is selected from amino, aminomethyl, aminoethyl, aminopropyl, CH₂ OH,CH₂ OCOCH₃, CH₂ Cl, CH₂ OCH₃, CH₂ OCH(CH₃)₂, F, Cl, Br, I, CHO, CH₂ CO₂H CH(CH₃)CO₂ H, --CO₂ CH₃, --CONH₂, --CONHCH₃, CON(CH₃)₂, --CH₂ NHCO₂ C₂H₅, ##STR241## CH₂ NHCO₂ CH₃, --CH₂ NHCO₂ C₃ H₇, --CH₂ NHCO₂ CH₂ (CH₃)₂,--CH₂ NHCO₂ C₄ H₉, CH₂ NHCO₂ -adamantyl, --CH₂ NHCO₂ --(1-naphthyl),--CH₂ NHCONHCH₃, --CH₂ NHCONHC₂ H₅, --CH₂ NHCONHC₃ H₇, --CH₂ NHCONHC₄H₉, --CH₂ NHCONHCH(CH₃)₂, --CH₂ NHCONH(1-naphthyl), --CH₂NHCONH(1-adamantyl), CO₂ H, --CH₂ CH₂ CH₂ CO₂ H, --CH₂ CH₂ F, --CH₂OCONHCH₃, --CH₂ CH₂ CH₂ F, --CH₂ SH and ##STR242## with the proviso thatat least one of R⁵, R⁶, R⁸ and R⁹ is an acidic group selected from COOHand ##STR243## and wherein each of the remainder of R³ through R¹¹ ishydrido, with the further proviso that at least one of said R¹ throughR¹¹ is a substituent selected from COOH and moieties containing aterminal primary or secondary amino group; or a tautomer thereof or apharmaceutically-acceptable salt thereof.
 18. The composition of claim16 wherein each G substituent is hydroxy.
 19. The composition of claim16 wherein each G substituent is hydroxy; wherein R⁵⁰ is hydrido; andwherein R⁵¹ is selected from ##STR244## wherein R⁵⁵ is selected frommethyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl,tert-butyl, n-pentyl, neopentyl, n-hexyl and chloromethyl.
 20. Thecomposition of claim 16 wherein said second radical is ##STR245## 21.The composition of claim 16 wherein said first radical is abiphenylalkyl 1H-substituted-1,3-imidazole angiotensin II antagonistcompound containing a terminal primary or secondary amino moietyattached at one of said R¹ through R¹¹ positions of Formula I, saidamino moiety selected from amino and linear or branched aminoalkylmoieties containing linear or branched alkyl groups selected fromaminomethyl, aminoethyl, aminopropyl, aminoisopropyl, aminobutyl,aminosecbutyl, aminoisobutyl, aminotertbutyl, aminopentyl,aminoisopentyl and aminoneopentyl.
 22. The composition of claim 21wherein each of R²⁰⁰ and R²⁰¹ is hydrido.
 23. The composition of claim16 wherein said angiotensin II antagonist compound is4'-[2-butyl-5-chloro-4-(hydroxymethyl)-1H-imidazol-1-ylmethyl][1,1'-biphenyl]-2-carboxylicacid or a pharmaceutically-acceptable salt thereof.
 24. The compositionof claim 23 wherein said conjugate is N-acetyl-L-glutamic acid,5-[[4'-[2-butyl-5-chloro-4-(hydroxymethyl)-1H-imidazol-1-ylmethyl][1,1'-biphenyl]-2-yl]carbonyl]hydrazideor a pharmaceutically-acceptable salt thereof.
 25. The composition ofclaim 23 wherein said conjugate is N²-acetyl-N-[[2-butyl-5-chloro-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazol-4-yl]methyl]-L-glutamineor a pharmaceutically-acceptable salt thereof.
 26. The composition ofclaim 23 wherein said conjugate is N-acetyl-N-L-glutamic acid,5-[2-butyl-5-chloro-1-[[2'-(1H-tetrazol-5-yl)[1,1-biphenyl]-4-yl]methyl]-1H-imidazol-4-yl]acetylhydrazideor a pharmaceutically-acceptable salt thereof.
 27. The composition ofclaim 16 wherein said angiotensin II antagonist compound is4'-[2-butyl-4-chloro-5-(hydroxymethyl)-1H-imidazol-1-ylmethyl][1,1'-biphenyl]-2-carboxylicacid or a pharmaceutically-acceptable salt thereof.
 28. The compositionof claim 12 wherein said conjugate is N-acetyl-L-glutamic acid,5-[[4'-[2-butyl-4-chloro-5-(hydroxymethyl)-1H-imidazol-1-ylmethyl][1,1'-biphenyl]-2-yl]carbonyl]hydrazideor a pharmaceutically-acceptable salt thereof.
 29. The composition ofclaim 27 wherein said conjugate is N²-acetyl-N-[[2-butyl-4-chloro-1-[[2'-(1H-tetrazol-5-biphenyl-4-yl)methyl]-1H-imidazol-5-yl]methyl]-L-glutamineor a pharmaceutically-acceptable salt thereof.
 30. The composition ofclaim 27 wherein said conjugate is N-acetyl-L-glutamic acid,5-[2-butyl-4-chloro-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazol-5-yl]acetylhydrazideor a pharmaceutically-acceptable salt thereof.
 31. A method for treatinga circulator disorder, said method comprising administering to a patientafflicted with or susceptible to said disorder atherapeutically-effective amount of a renal-selective conjugate, saidrenal-selective conjugate consisting of a first radical and a secondradical, said first and second radicals connected together by akidney-enzyme-cleavable bond, wherein said first radical is provided bya biphenylalkyl 1H-substituted-1,3-imidazole angiotensin II antagonistcompound of Formula I: ##STR246## wherein m is one; wherein R⁰ isselected from C₄ H₉ (n), CH₃ CH₂ CH═CH, C₃ H₇ (N), SC₃ H₇, ##STR247## C₂H₅, C₅ H₁₁ (n), C₆ H₁₃ (n), SC₄ H₉, ##STR248## CH₃ CH═CH and CH₃ CH₂ CH₂CH═CH--; wherein R¹ is selected from amino, aminomethyl, aminoethyl,aminopropyl, CH₂ OH, CH₂ OCOCH₃, CH₂ Cl, F, Cl, Br, I, CH₂ OCH₃, CH₂OCH(CH₃)₂, CHO, CH₂ CO₂ H, CH(CH₃)CO₂ H, --CO₂ CH₃, --CONH₂, --CONHCH₃,CON(CH₃)₂, --CH₂ --NHCO₂ C₂ H₅, ##STR249## --CH₂ NHCO₂ CH₃, --CH₂ NHCO₂C₃ H₇, --CH₂ NHCO₂ CH₂ (CH₃) ₂, --CH₂ NHCO₂ C₄ H₉, CH₂ NHCO₂ -adamantyl,--CH₂ NHCO₂ -(1-naphthyl), --CH₂ NHCONHCH₃, --CH₂ NHCONHC₂ H₅, --CH₂NHCONHC₃ H₇, --CH₂ NHCONHC₄ H₉, --CH₂ NHCONHCH(CH₃)₂, --CH₂NHCONH(1-naphthyl), --CH₂ NHCONH(1-adamantyl), --CH₂ CH₂ CH₂ CO₂ H,--CH₂ CH₂ F, --CH₂ OCONHCH₃, --CH₂ CH₂ CH₂ F, --CH₂ SH and ##STR250##wherein R² is selected from H, F, Cl, Br, I, NO₂, CF₃, CH₂ OH, methyl,ethyl, n-propyl, isoproyl, n-butyl, sec-butyl, isobutyl, tert-butyl,n-pentyl, isopentyl, neopentyl, phenyl, benzyl, phenethyl, cyclohexyl,cyclohexylmethyl, 1-oxoethyl, 1-oxopropyl, 1-oxobutyl, 1-oxopentyl,1,1-dimethoxypropyl, 1,1-dimethoxybutyl, 1,1-dimethoxypentyl,hydroxyalkyl, difluoromethyl, 1,1-difluoroethyl, 1,1-difluoropropyl,1,1-difluorobutyl and 1,1-difluoropentyl; with the proviso that at leastone of R⁵, R⁶, R⁸ and R⁹ is an acidic group selected from CO₂ H, SH, SO₃H and ##STR251## and wherein each of the remainder of R³ through R¹¹ ishydrido, with the further proviso that at least one of said R¹ throughR¹¹ is a substituent selected from COOH and moieties containing aterminal primary or secondary amino group; or a tautomer thereof or apharmaceutically-acceptable salt thereof;wherein said second radical isprovided by a compound selected from a class of compounds of Formula II:##STR252## wherein each of R⁵⁰ and R⁵¹ may be independently selectedfrom hydrido, alkylcarbonyl, alkoxycarbonyl, alkoxyalkyl, hydroxyalkyland haloalkyl; and wherein G is selected from hydrido, hydroxyl, halo,mercapto, --OR⁵², --SR⁵³ and ##STR253## with each of R⁵², R⁵³ and R⁵⁴independently selected from alkyl, and wherein each of R⁵³ and R⁵⁴ maybe further independently selected from hydrido; with the proviso thatsaid kidney-enzyme-cleavable bond is within an amide group formedbetween said first and second radicals, wherein said first radical has aterminal primary or secondary amino moiety, wherein said first-radicalamino moiety is provided by one of said R¹ through R¹¹ substituents ofsaid Formula I compound or is provided by a linking moiety attached to acarbonyl group attached at one of said R¹ through R¹¹ substituents ofsaid Formula I, and wherein said second radical has a carbonyl moietyattached at the gamma-position carbon of said Formula II compound,whereby said amide bond is formed from said first-radical amino moietyand said second radical carbonyl moiety; and wherein said linking moietyis a divalent radical of Formula III: ##STR254## wherein each of R²⁰⁰and R²⁰¹ may be independently selected from hydrido, alkyl, cycloaklyl,cycloalkylalkyl, alkoxyalkyl, hydroxyalkyl and haloalkyl; and wherein nis a number selected from zero through six, inclusive; or apharmaceutically-acceptable salt of said renal-selective conjugate. 32.The composition of claim 16 wherein m is one; wherein R⁰ is selectedfrom C₄ H₉ (n), CH₃ CH₂ CH═CH, C₃ H₇ (N), SC₃ H₇, ##STR255## C₂ H₅, C₅H₁₁ (n), C₆ H₁₃ (n), SC₄ H₉, ##STR256## CH₃ CH═CH and CH₃ CH₂ CH₂CH═CH--; wherein R¹ is selected from H, NO₂, CF₃, CH₂ OH, F, Cl, Br, I,methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl,tert-butyl, n-pentyl, isopentyl, neopentyl, phenyl, benzyl, phenethyl,cyclohexyl, cyclohexylmethyl, 1-oxoethyl, 1-oxopropyl, 1-oxobutyl,1-oxopentyl, 1,1-dimethoxypropyl, 1,1-dimethoxybutyl,1,1-dimethoxypentyl, hydroxyalkyl, difluoromethyl, 1,1-difluoroethyl,1,1-difluoropropyl, 1,1-difluorobutyl and 1,1-difluoropenyl; wherein R²is selected from amino, aminomethyl, aminoethyl, aminopropyl, CH₂ OH,CH₂ OCOCH₃, CH₂ Cl, CH₂ OCH₃, CH₂ OCH(CH₃)₂, F, Cl, Br, I, CHO, CH₂ CO₂H CH(CH₃)CO₂ H, --CO₂ CH₃, --CONH₂, --CONHCH₃, CON(CH₃)₂, --CH₂ NHCO₂ C₂H₅, ##STR257## CH₂ NHCO₂ CH₃, --CH₂ NHCO₂ C₃ H₇, --CH₂ NHCO₂ CH₂ (CH₃)₂,--CH₂ NHCO₂ C₄ H₉, CH₂ NHCO₂ -adamantyl, --CH₂ NHCO₂ --(1-naphthyl),--CH₂ NHCONHCH₃, --CH₂ NHCONHC₂ H₅, --CH₂ NHCONHC₃ H₇, --CH₂ NHCONHC₄H₉, --CH₂ NHCONHCH(CH₃)₂, --CH₂ NHCONH(1-naphthyl), --CH₂NHCONH(1-adamantyl), CO₂ H, --CH₂ CH₂ CH₂ CO₂ H, --CH₂ CH₂ F, --CH₂OCONHCH₃, --CH₂ CH₂ CH₂ F, --CH₂ SH and ##STR258## with the proviso thatat least one of R⁵, R⁶, R⁸ and R⁹ is an acidic group selected from COOHand ##STR259## and wherein each of the remainder of R³ through R¹¹ ishydrido, with the further proviso that at least one of said R¹ throughR¹¹ is a substituent selected from COOH and moieties containing aterminal primary or secondary amino group; or a tautomer thereof or apharmaceutically-acceptable salt thereof.
 33. The composition of claim31 wherein each G substituent is hydroxy.
 34. The composition of claim33 wherein each G substituent is hydroxy; wherein R⁵⁰ is hydrido; andwherein R⁵¹ is selected from ##STR260## wherein R⁵⁵ is selected frommethyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl,tert-butyl, n-pentyl, neopentyl, n-hexyl and chloromethyl.
 35. Thecomposition of claim 31 wherein said second radical is ##STR261## 36.The composition of claim 31 wherein said first radical is abiphenylalkyl 1H-substituted-1,3-imidazole angiotensin II antagonistcompound containing a terminal primary or secondary amino moietyattached at one of said R¹ through R¹¹ positions of Formula I, saidamino moiety selected from amino and linear or branched aminoalkylmoieties containing linear or branched alkyl groups selected fromaminomethyl, aminoethyl, aminopropyl, aminoisopropyl, aminobutyl,aminosecbutyl, aminoisobutyl, aminotertbutyl, aminopentyl,aminoisopentyl and aminoneopentyl.
 37. The composition of claim 31wherein each of R²⁰⁰ and R²⁰¹ is hydrido.
 38. The composition of claim31 wherein said angiotensin II antagonist compound is4'-[2-butyl-5-chloro-4-(hydroxymethyl)-1H-imidazol-1-ylmethyl][1,1'-biphenyl]-2-carboxylicacid or a pharmaceutically-acceptable salt thereof.
 39. The method ofclaim 38 wherein said conjugate is N-acetyl-L-glutamic acid,5-[[4'-[2-butyl-5-chloro-4-(hydroxymethyl)-1H-imidazol-1-ylmethyl][1,1'-biphenyl]-2-yl]carbonyl]hydrazideor a pharmaceutically-acceptable salt thereof.
 40. The method of claim38 wherein said conjugate is N²-acetyl-N-[[2-butyl-5-chloro-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazol-4-yl]methyl]-L-glutamineor a pharmaceutically-acceptable salt thereof.
 41. The method of claim38 wherein said conjugate is N-acetyl-N-L-glutamic acid,5-[2-butyl-5-chloro-1-[[2'-(1H-tetrazol-5-yl)[1,1-biphenyl]-4-yl]methyl]-1H-imidazol-4-yl]acetylhydrazideor a pharmaceutically-acceptable salt thereof.
 42. The method of claim31 wherein said angiotensin II antagonist compound is4'-[2-butyl-4-chloro-5-(hydroxymethyl)-1H-imidazol-1-ylmethyl][1,1'-biphenyl]-2-carboxylicacid or a pharmaceutically-acceptable salt thereof.
 43. The method ofclaim 42 wherein said conjugate is N-acetyl-L-glutamic acid,5-[[4'-[2-butyl-4-chloro-5-(hydroxymethyl)-1H-imidazol-1-ylmethyl][1,1'-biphenyl]-2-yl]carbonyl]hydrazideor a pharmaceutically-acceptable salt thereof.
 44. The method of claim42 wherein said conjugate is N²-acetyl-N-[[2-butyl-4-chloro-1-[[2'-(1H-tetrazol-5-biphenyl-4-yl)methyl]-1H-imidazol-5-yl]methyl]-L-glutamineor a pharmaceutically-acceptable salt thereof.
 45. The method of claim42 wherein said conjugate is N-acetyl-L-glutamic acid,5-[2-butyl-4-chloro-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazol-5-yl]acetylhydrazideor a pharmaceutically-acceptable salt thereof.
 46. The method of claim31 wherein said circulatory disorder is a hypertensive-related disorder.47. The method of claim 46 wherein said hypertensive-related disorder ischronic hypertension.